|
1
|
Rao G, Mack CD, Nguyen T, Wong N, Payne K, Worley L, Gray PE, Wong M, Hsu P, Stormon MO, Preece K, Suan D, O'Sullivan M, Blincoe AK, Sinclair J, Okada S, Hambleton S, Arkwright PD, Boztug K, Stepensky P, Cooper MA, Bezrodnik L, Nadeau KC, Abolhassani H, Abraham RS, Seppänen MRJ, Béziat V, Bustamante J, Forbes Satter LR, Leiding JW, Meyts I, Jouanguy E, Boisson-Dupuis S, Uzel G, Puel A, Casanova JL, Tangye SG, Ma CS. Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 + IL-9-expressing cells. J Allergy Clin Immunol 2025; 155:1161-1178. [PMID: 39622295 PMCID: PMC11972900 DOI: 10.1016/j.jaci.2024.11.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 12/22/2024]
Abstract
BACKGROUND CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T-cell subsets-TH1, TH2, TH17, TH22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing TH9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human TH9 cells remain incompletely defined. OBJECTIVE We sought to define signaling pathways that regulate IL-9 production by human CD4+ T cells. METHODS Human naive and memory CD4+ T cells were cultured under different conditions, and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4+ T cells from a broad range of patients (n = 92) with pathogenic variants in key immune genes (n = 21) to differentiate into IL-9+ cells. RESULTS We identified 2 culture conditions that yielded IL-9-expressing cells from naive CD4+ T cells and amplified IL-9 production by in vivo-generated memory CD4+ T cells: TGF-β plus IL-4 (ie, TH9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, TH17 polarizing condition). Combining these conditions had a synergistic effect in generating IL-9+CD4+ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signaling via the T-cell receptor and STAT5. Importantly, IL-9 induction was restrained by IFN-γ/STAT1 and IL-10. CONCLUSIONS Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4+ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.
Collapse
Affiliation(s)
- Geetha Rao
- Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Corinne D Mack
- Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Tina Nguyen
- Garvan Institute of Medical Research, Darlinghurst, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia
| | - Natalie Wong
- Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Kathryn Payne
- Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Lisa Worley
- Garvan Institute of Medical Research, Darlinghurst, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia
| | - Paul E Gray
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, Australia; School of Women's and Children's Health, UNSW Sydney, Sydney, Australia
| | - Melanie Wong
- Children's Hospital at Westmead, Westmead, Australia; Faculty of Medicine, University of Sydney, Sydney, Australia
| | - Peter Hsu
- Children's Hospital at Westmead, Westmead, Australia; Faculty of Medicine, University of Sydney, Sydney, Australia
| | | | - Kahn Preece
- John Hunter Children's Hospital, Newcastle, Australia
| | - Daniel Suan
- Garvan Institute of Medical Research, Darlinghurst, Australia
| | | | | | - Jan Sinclair
- Starship Children's Hospital, Auckland, New Zealand
| | - Satoshi Okada
- Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Sophie Hambleton
- Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Peter D Arkwright
- Lydia Becker Institute for Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Kaan Boztug
- St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; Medical University of Vienna, Department of Paediatrics and Adolescent Medicine, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Polina Stepensky
- Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
| | - Megan A Cooper
- Department of Pediatrics, Division of Rheumatology/Immunology, Washington University School of Medicine, St Louis, Mo
| | - Liliana Bezrodnik
- Grupo de Inmunología-Instituto Multidisciplinario de Investigaciones en Patologias Pediatricas (IMIPP-CONICET), Hospital de Niños "Dr. Ricardo Gutierrez," Buenos Aires, Argentina; Center for Clinical Immunology, Buenos Aires, Argentina
| | - Kari C Nadeau
- Sean N. Parker Center for Allergy and Asthma Research, Stanford, Calif; Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, Calif
| | - Hassan Abolhassani
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Roshini S Abraham
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
| | - Mikko R J Seppänen
- Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; ERN-RITA Core Center, RITAFIN, Helsinki, Finland
| | - Vivien Béziat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France
| | - Lisa R Forbes Satter
- Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, William T. Shearer Center for Human Immunobiology, Department of Allergy, Immunology, and Retrovirology, Houston, Tex
| | - Jennifer W Leiding
- Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, Md; Institute for Clinical and Translational Research and the Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St Petersburg, Fla
| | - Isabelle Meyts
- Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium; Department of Pediatrics, Division of Inborn Errors of Immunity, University Hospitals Leuven, Leuven, Belgium; FWO Vlaanderen, Brussels, Belgium
| | - Emmanuelle Jouanguy
- Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France
| | - Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Gulbu Uzel
- Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Imagine Institute, Université Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY; Howard Hughes Medical Institute, New York, NY; Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
| | - Stuart G Tangye
- Garvan Institute of Medical Research, Darlinghurst, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia
| | - Cindy S Ma
- Garvan Institute of Medical Research, Darlinghurst, Australia; School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Sydney, Australia.
| |
Collapse
|
|
2
|
Li T, Li Q, Liu S, Cao J, Mei J, Gong J, Chen J, Wang X, Zhang R, Li X, Wang Q, Zhang H, Wang B, Cao H, Yang H, Fung SY. Targeted V-type peptide-decorated nanoparticles prevent colitis by inhibiting endosomal TLR signaling and modulating intestinal macrophage polarization. Biomaterials 2025; 314:122843. [PMID: 39321686 DOI: 10.1016/j.biomaterials.2024.122843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 08/26/2024] [Accepted: 09/14/2024] [Indexed: 09/27/2024]
Abstract
Inflammatory bowel disease (IBD) has become a serious and challenging health problem globally without curative medical treatments. Mounting evidence suggests that intestinal macrophages and their phenotypes are key players in the pathogenesis of IBD. Modulating the phenotypes and functions of intestinal macrophages through targeted interventions could be a promising approach to manage detrimental gut inflammation in IBD. In this study, we rationally design and fabricate a novel class of V-type peptide-decorated nanoparticles, VP-NP, with potent anti-inflammatory activity. Such a design allows two functional motifs FFD in a single peptide molecule to enhance the bioactivity of the nanoparticles. As expected, VP-NP exhibits a strong inhibitory activity on endosomal Toll-like receptor (TLR) signaling. Surprisingly, VP-NP can inhibit M1 polarization while facilitating M2 polarization in mouse bone marrow-derived macrophages through regulating the key transcription factors NF-κB, STAT1 and PPAR-γ. Mechanistically, VP-NP is internalized by macrophages in the endosomes, where it blocks endosomal acidification to inhibit endosomal TLR signaling; the transcriptomic analysis reveals that VP-NP potently down-regulates many genes in TLR, NF-κB, JAK-STAT, and cytokine/chemokine signaling pathways associated with inflammatory responses. In a colitis mouse model, the intraperitoneally administered VP-NP effectively alleviates the disease activities by decreasing colon inflammation and injuries, pro-inflammatory cytokine production, and myeloid cell infiltration in the gut. Furthermore, VP-NP primarily targets intestinal macrophages and alters their phenotypes from inflammatory M1-type toward the anti-inflammatory M2-type. This study provides a new nanotherapeutic strategy to specifically regulate macrophage activation and phenotypes through a dual mechanism to control gut inflammation, which may augment current clinical treatments for IBD.
Collapse
Affiliation(s)
- Tongxuan Li
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Qianqian Li
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Sixia Liu
- The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Intensive Care Unit of the Second Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Jiazhu Cao
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Jian Mei
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Jiameng Gong
- The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Intensive Care Unit of the Second Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Jiugeng Chen
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoyu Wang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Rui Zhang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Xiaomeng Li
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Qian Wang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Hefan Zhang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
| | - Hong Yang
- The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Intensive Care Unit of the Second Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China.
| | - Shan-Yu Fung
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Immunology, School of Basic Medical Science, Department of Gastroenterology and Hepatology, General Hospital, International Joint Laboratory of Ocular Diseases, Ministry of Education, Tianjin Medical University, Tianjin, China.
| |
Collapse
|
|
3
|
Badii M, Nica V, Straton AR, Kischkel B, Gaal O, Cabău G, Klück V, Hotea I, Novakovic B, Pamfil C, Rednic S, Netea MG, Popp RA, Joosten LAB, Crișan TO. Downregulation of type I interferon signalling pathway by urate in primary human PBMCs. Immunology 2025; 174:100-112. [PMID: 39354748 PMCID: PMC11652411 DOI: 10.1111/imm.13858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 08/23/2024] [Indexed: 10/03/2024] Open
Abstract
Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-β were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-β did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.
Collapse
Affiliation(s)
- Medeea Badii
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Valentin Nica
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Ancuța R. Straton
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Brenda Kischkel
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Orsolya Gaal
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Georgiana Cabău
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Viola Klück
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Ioana Hotea
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Boris Novakovic
- Murdoch Children's Research Institute and Department of PaediatricsUniversity of Melbourne, Royal Children's HospitalParkvilleVictoriaAustralia
| | - Cristina Pamfil
- Department of RheumatologyIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Simona Rednic
- Department of RheumatologyIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Mihai G. Netea
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Radu A. Popp
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Leo A. B. Joosten
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Tania O. Crișan
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| |
Collapse
|
|
4
|
Wang ZY, Gao ST, Gou XJ, Qiu FR, Feng Q. IL-1 receptor-associated kinase family proteins: An overview of their role in liver disease. Eur J Pharmacol 2024; 978:176773. [PMID: 38936453 DOI: 10.1016/j.ejphar.2024.176773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/16/2024] [Accepted: 06/23/2024] [Indexed: 06/29/2024]
Abstract
The interleukin-1 receptor-associated kinase (IRAK) family is a group of serine-threonine kinases that regulates various cellular processes via toll-like receptor (TLR)/interleukin-1 receptor (IL1R)-mediated signaling. The IRAK family comprises four members, including IRAK1, IRAK2, IRAK3, and IRAK4, which play an important role in the expression of various inflammatory genes, thereby contributing to the inflammatory response. IRAKs are key proteins in chronic and acute liver diseases, and recent evidence has implicated IRAK family proteins (IRAK1, IRAK3, and IRAK4) in the progression of liver-related disorders, including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis virus infection, acute liver failure, liver ischemia-reperfusion injury, and hepatocellular carcinoma. In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.
Collapse
Affiliation(s)
- Zhuo-Yuan Wang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Si-Ting Gao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao-Jun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China
| | - Fu-Rong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, 201203, China.
| |
Collapse
|
|
5
|
Ngo C, Garrec C, Tomasello E, Dalod M. The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond. Cell Mol Immunol 2024; 21:1008-1035. [PMID: 38777879 PMCID: PMC11364676 DOI: 10.1038/s41423-024-01167-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/10/2024] [Indexed: 05/25/2024] Open
Abstract
Type I and III interferons (IFNs) are essential for antiviral immunity and act through two different but complimentary pathways. First, IFNs activate intracellular antimicrobial programs by triggering the upregulation of a broad repertoire of viral restriction factors. Second, IFNs activate innate and adaptive immunity. Dysregulation of IFN production can lead to severe immune system dysfunction. It is thus crucial to identify and characterize the cellular sources of IFNs, their effects, and their regulation to promote their beneficial effects and limit their detrimental effects, which can depend on the nature of the infected or diseased tissues, as we will discuss. Plasmacytoid dendritic cells (pDCs) can produce large amounts of all IFN subtypes during viral infection. pDCs are resistant to infection by many different viruses, thus inhibiting the immune evasion mechanisms of viruses that target IFN production or their downstream responses. Therefore, pDCs are considered essential for the control of viral infections and the establishment of protective immunity. A thorough bibliographical survey showed that, in most viral infections, despite being major IFN producers, pDCs are actually dispensable for host resistance, which is achieved by multiple IFN sources depending on the tissue. Moreover, primary innate and adaptive antiviral immune responses are only transiently affected in the absence of pDCs. More surprisingly, pDCs and their IFNs can be detrimental in some viral infections or autoimmune diseases. This makes the conservation of pDCs during vertebrate evolution an enigma and thus raises outstanding questions about their role not only in viral infections but also in other diseases and under physiological conditions.
Collapse
Affiliation(s)
- Clémence Ngo
- Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France
| | - Clémence Garrec
- Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France
| | - Elena Tomasello
- Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France.
| | - Marc Dalod
- Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France.
| |
Collapse
|
|
6
|
Abdolmohammadi-Vahid S, Baradaran B, Sadeghi A, Bezemer GFG, Kiaee F, Adcock IM, Folkerts G, Garssen J, Mortaz E. Effects of toll-like receptor agonists and SARS-CoV-2 antigens on interferon (IFN) expression by peripheral blood CD3 + T cells from COVID-19 patients. Exp Mol Pathol 2024; 137:104897. [PMID: 38691979 DOI: 10.1016/j.yexmp.2024.104897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 03/09/2024] [Accepted: 04/22/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND Signaling by toll-like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. MATERIAL & METHODS 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex-matched healthy control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8, and 9 agonists, the spike protein (SP) of SARS-CoV-2, and the receptor binding domain (RBD) of SP. Frequencies of CD3+IFN-β+ T cells, and CD3+IFN-γ+ T cells were evaluated by flow cytometry. Interferon (IFN)-β gene expression was assessed by qRT-PCR. RESULTS The frequency of CD3+IFN-β+ T cells was higher in PBMCs from moderate (p < 0.0001) and severe (p = 0.009) patients at baseline in comparison with HCs. The highest increase in the frequency of CD3+IFN-β+ T cells in cell from moderate patients was induced by TLR8 agonist and SP (p < 0.0001 for both) when compared to HC, while, the highest increase of the frequency of CD3+IFN-β+ T cells in sample of severe patients was seen with TLR8 and TLR7 agonists (both p = 0.002). The frequency of CD3+IFN-γ+ T cells was significantly increased upon stimulation with TLR agonists in cell from patients with moderate and severe COVID-19, compared with HC (all p < 0.01), except with TLR7 and TLR8 agonists. The TLR8 agonist did not significantly increase the frequency of CD3+IFN-γ+ T cells in PBMCs of severe patients, but did so in cells from patients with moderate disease (p = 0.01). Moreover, IFN-β gene expression was significantly upregulated in CD3+T cells from moderate (p < 0.0001) and severe (p = 0.002) COVID-19 patients, compared to HC after stimulation with the TLR8 agonist, while, stimulation of T cells with SP, significantly up-regulated IFN-β mRNA expression in cells from patients with moderate (p = 0.0003), but not severe disease. CONCLUSION Stimulation of PBMCs from COVID-19 patients, especially patients with moderate disease, with TLR8 agonist and SP increased the frequency of IFN-β-producing T cells and IFN-β gene expression.
Collapse
Affiliation(s)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armin Sadeghi
- Tuberculosis and Lung Disease Research Center of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gillina F G Bezemer
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Impact Station, Hilversum, the Netherlands
| | - Fatemeh Kiaee
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ian M Adcock
- Respiratory Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom; Immune Health Program at Hunter Medical Research Institute and the College of Health and Medicine at the University of Newcastle, NSW, Australia
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Esmaeil Mortaz
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
7
|
Zhang Q, Kisand K, Feng Y, Rinchai D, Jouanguy E, Cobat A, Casanova JL, Zhang SY. In search of a function for human type III interferons: insights from inherited and acquired deficits. Curr Opin Immunol 2024; 87:102427. [PMID: 38781720 PMCID: PMC11209856 DOI: 10.1016/j.coi.2024.102427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 03/19/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024]
Abstract
The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.
Collapse
Affiliation(s)
- Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
| | - Kai Kisand
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Yi Feng
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
| | - Darawan Rinchai
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
| | - Aurélie Cobat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, USA
| | - Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France
| |
Collapse
|
|
8
|
Izadi S, Najfizadeh SR, Nejati A, TeimooriRad M, Shahmahmoodi S, Shirazi FG, Shokri F, Marashi SM. Potential role of EBV and Toll-like receptor 9 ligand in patients with systemic lupus erythematosus. Immunol Res 2023; 71:698-708. [PMID: 37097524 DOI: 10.1007/s12026-023-09380-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/01/2023] [Indexed: 04/26/2023]
Abstract
SLE is a multisystem autoimmune disease characterized by multiple immunological abnormalities including production of autoantibodies. While the etiology of SLE is largely unknown, it is generally accepted that both genetic and environmental factors contribute to disease risk and immune dysregulation. Production of IFN-α is important for protecting the host against infections; however, over stimulation of innate immune pathways can induce autoimmune disease. Environmental factors, particularly Epstein-Barr virus (EBV), have been proposed to play an important role in SLE disease. Improper engagement of Toll-like receptor (TLR) pathways by endogenous or exogenous ligands may lead to the initiation of autoimmune responses and tissue injury. EBV is shown to be a potent stimulant of IFN-α by TLR signaling cascades. Given the highlighted role of IFN-α in SLE pathogenesis and potential role of EBV infection in this disease, the present study is aimed at exploring the in vitro effects of EBV infection and CPG (either alone or in combination) on IFN-α. We also examined the expression level of CD20 and BDCA-4 and CD123 in PBMCs in 32 SLE patients and 32 healthy controls. Our results showed PBMCs treated with CPG-induced higher levels of IFN-α and TLR-9 gene expression fold change compared to cells treated with either EBV or EBV-CPG. Moreover, PBMCs treated with CPG produced significantly higher IFN-α concentration in supernatant compared to cells treated with EBV but not EBV-CPG. Our results further highlight the potential role of EBV infection and TLRs in SLE patients although more studies are warranted to ascertain the global imprint that EBV infection can have on immune signature in patients with SLE.
Collapse
Affiliation(s)
- Shima Izadi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14155, Iran
| | - Sayed Reza Najfizadeh
- Rheumatology Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Nejati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14155, Iran
| | - Majid TeimooriRad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14155, Iran
| | - Shohreh Shahmahmoodi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14155, Iran
| | - Frough Golsaz Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed Mahdi Marashi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14155, Iran.
| |
Collapse
|
|
9
|
García-García A, Pérez de Diego R, Flores C, Rinchai D, Solé-Violán J, Deyà-Martínez À, García-Solis B, Lorenzo-Salazar JM, Hernández-Brito E, Lanz AL, Moens L, Bucciol G, Almuqamam M, Domachowske JB, Colino E, Santos-Perez JL, Marco FM, Pignata C, Bousfiha A, Turvey SE, Bauer S, Haerynck F, Ocejo-Vinyals JG, Lendinez F, Prader S, Naumann-Bartsch N, Pachlopnik Schmid J, Biggs CM, Hildebrand K, Dreesman A, Cárdenes MÁ, Ailal F, Benhsaien I, Giardino G, Molina-Fuentes A, Fortuny C, Madhavarapu S, Conway DH, Prando C, Schidlowski L, Martínez de Saavedra Álvarez MT, Alfaro R, Rodríguez de Castro F, Meyts I, Hauck F, Puel A, Bastard P, Boisson B, Jouanguy E, Abel L, Cobat A, Zhang Q, Casanova JL, Alsina L, Rodríguez-Gallego C. Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia. J Exp Med 2023; 220:e20220170. [PMID: 36880831 PMCID: PMC9998661 DOI: 10.1084/jem.20220170] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 11/11/2022] [Accepted: 01/30/2023] [Indexed: 03/08/2023] Open
Abstract
X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.
Collapse
Affiliation(s)
- Ana García-García
- Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Barcelona, Spain
| | - Rebeca Pérez de Diego
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - Carlos Flores
- Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain
- Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Dept. of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
| | - Darawan Rinchai
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
| | - Jordi Solé-Violán
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Dept. of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
- Dept. of Intensive Care Medicine, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
| | - Àngela Deyà-Martínez
- Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Barcelona, Spain
| | - Blanca García-Solis
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - José M. Lorenzo-Salazar
- Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain
| | - Elisa Hernández-Brito
- Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
| | - Anna-Lisa Lanz
- Dept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Leen Moens
- Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven, Leuven, Belgium
| | - Giorgia Bucciol
- Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven, Leuven, Belgium
- Dept. of Pediatrics, Childhood Immunology, UZ Leuven, Leuven, Belgium
| | - Mohamed Almuqamam
- Dept. of Pediatrics, Drexel University College of Medicine, St Christopher’s Hospital for Children, Philadelphia, PA, USA
| | | | - Elena Colino
- Unidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas de Gran Canaria, Spain
| | - Juan Luis Santos-Perez
- Unidad de Gestión Clínica de Pediatría y Cirugía Pediátrica, Hospital Virgen de las Nieves-IBS, Granada, Spain
| | - Francisco M. Marco
- Dept. of Immunology, Alicante University General Hospital Doctor Balmis, Alicante, Spain
- Alicante Institute for Health and Biomedical Research, Alicante, Spain
| | - Claudio Pignata
- Dept. of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy
| | - Aziz Bousfiha
- Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital, Casablanca, Morocco
- Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Stuart E. Turvey
- Dept. of Paediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Stefanie Bauer
- Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen, Erlangen, Germany
| | - Filomeen Haerynck
- Dept. of Pediatric Immunology and Pulmonology, Centre for Primary Immune Deficiency Ghent, Ghent University Hospital, Ghent, Belgium
- Dept. of Internal Medicine and Pediatrics, PID Research Laboratory, Ghent University, Ghent, Belgium
| | | | - Francisco Lendinez
- Dept. of Pediatric Oncohematology, Hospital Materno Infantil Torrecárdenas, Almería, Spain
| | - Seraina Prader
- Division of Immunology and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
| | - Nora Naumann-Bartsch
- Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen, Erlangen, Germany
| | - Jana Pachlopnik Schmid
- Division of Immunology and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland
| | - Catherine M. Biggs
- Dept. of Paediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | - Kyla Hildebrand
- Dept. of Paediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
| | | | - Miguel Ángel Cárdenes
- Dept. of Internal Medicine, Unit of Infectious Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
| | - Fatima Ailal
- Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital, Casablanca, Morocco
- Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Ibtihal Benhsaien
- Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital, Casablanca, Morocco
- Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Giuliana Giardino
- Dept. of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy
| | | | - Claudia Fortuny
- Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona, Barcelona, Spain
- Pediatric Infectious Diseases Unit, Hospital Sant Joan de Déu, Barcelona, Spain
- CIBER of Epidemiology and Public Health, Madrid, Spain; Translational Research Network in Pediatric Infectious Diseases, Madrid, Spain
- Dept. of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, University of Barcelona, Barcelona, Spain
| | - Swetha Madhavarapu
- Dept. of Pediatrics, Drexel University College of Medicine, St Christopher’s Hospital for Children, Philadelphia, PA, USA
| | - Daniel H. Conway
- Dept. of Pediatrics, Drexel University College of Medicine, St Christopher’s Hospital for Children, Philadelphia, PA, USA
| | - Carolina Prando
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe, Curitiba, Brazil
| | - Laire Schidlowski
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe, Curitiba, Brazil
| | | | - Rafael Alfaro
- Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
| | - Felipe Rodríguez de Castro
- Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
- Dept. of Respiratory Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
| | - Isabelle Meyts
- Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven, Leuven, Belgium
- Dept. of Pediatrics, Childhood Immunology, UZ Leuven, Leuven, Belgium
| | - Fabian Hauck
- Dept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Paul Bastard
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
- Pediatric Hematology and Immunology Unit, Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University Paris Cité, Imagine Institute, Paris, France
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
- Howard Hughes Medical Institute, New York, NY, USA
| | - Laia Alsina
- Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona, Barcelona, Spain
- Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona, Barcelona, Spain
- Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Barcelona, Spain
- Dept. of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, University of Barcelona, Barcelona, Spain
| | - Carlos Rodríguez-Gallego
- Dept. of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
- Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain
- Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| |
Collapse
|
|
10
|
Tepe ZG, Yazıcı YY, Tank U, Köse LI, Özer M, Aytekin C, Belkaya S. Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis. J Clin Immunol 2023; 43:192-205. [PMID: 36205835 PMCID: PMC9540208 DOI: 10.1007/s10875-022-01369-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/14/2022] [Indexed: 01/21/2023]
Abstract
Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient's cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient's leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.
Collapse
Affiliation(s)
- Zeynep Güneş Tepe
- Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Yılmaz Yücehan Yazıcı
- Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Umut Tank
- Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Ladin Işık Köse
- Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Murat Özer
- Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Caner Aytekin
- Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Serkan Belkaya
- Department of Molecular Biology and Genetics, Faculty of Science, İhsan Doğramacı Bilkent University, Ankara, Turkey
| |
Collapse
|
|
11
|
Campbell NO, Davison LM, Banerjee S, Nguyen JK, Krafcik S, Silverman RH, Jorgensen TN. Ablation of SigH+ pDCs in B6.Nba2 mice prevents lupus-like disease development only if started before disease is fully established. Lupus 2022; 31:1619-1629. [PMID: 36134524 PMCID: PMC10466375 DOI: 10.1177/09612033221127561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Systemic lupus erythematosus is characterized by hyper-activation of the immune system, multi-organ inflammation, and end-organ damage. Type I interferons (IFN-I) have been strongly implicated a role in disease etiology as has the main IFN-I-producing cell subset, the plasmacytoid dendritic cell (pDC). The B6.Nba2 mouse model develops a lupus-like disease characterized by elevated IFN-I levels and pDC pathogenicity. We have previously shown that pDC ablation prior to disease development in B6.Nba2 mice effectively prevents disease; however, it remains unclear if a similar protection can be seen if pDC ablation is initiated during later disease stages. This is important as Systemic lupus erythematosus patients are rarely diagnosed until disease is well-established and thus preventative treatment is unlikely to take place. Here we show that ablation of pDCs in the B6.Nba2 mouse model must be initiated early in order to effectively block disease development and that sustained reduction in pDC numbers is necessary for sustained effects. Finally, targeting of pDCs have been hypothesized to affect immunity towards infectious agents, in particular virus and intracellular bacteria. We show here that pDC ablation in B6.Nba2 mice does not affect the anti-viral response to encephalomyocarditic virus or a model T-dependent antigen. In summary, pDC ablation does not affect general immunity, but needs to happen early and be sustained to prevent lupus-like disease development in B6.Nba2 mice.
Collapse
Affiliation(s)
- Nicole O Campbell
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
| | - Laura M Davison
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland OH, USA
- Amgen (Teneobio), Newark, CA, USA
| | - Shuvojit Banerjee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Autonomous Therapeutics, Inc., Rockville, MD, USA
| | - Jane K Nguyen
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Sarah Krafcik
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
| | - Robert H Silverman
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
| | - Trine N Jorgensen
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland OH, USA
| |
Collapse
|
|
12
|
Laurent P, Yang C, Rendeiro AF, Nilsson-Payant BE, Carrau L, Chandar V, Bram Y, tenOever BR, Elemento O, Ivashkiv LB, Schwartz RE, Barrat FJ. Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19. Sci Immunol 2022; 7:eadd4906. [PMID: 36083891 PMCID: PMC9853436 DOI: 10.1126/sciimmunol.add4906] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Lung-infiltrating macrophages create a marked inflammatory milieu in a subset of patients with COVID-19 by producing a cytokine storm, which correlates with increased lethality. However, these macrophages are largely not infected by SARS-CoV-2, so the mechanism underlying their activation in the lung is unclear. Type I interferons (IFN-I) contribute to protecting the host against SARS-CoV-2 but may also have some deleterious effect, and the source of IFN-I in the lungs of infected patients is not well defined. Plasmacytoid dendritic cells (pDCs), a key cell type involved in antiviral responses, can produce IFN-I in response to SARS-CoV-2. We observed the infiltration of pDCs in the lungs of SARS-CoV-2-infected patients, which correlated with strong IFN-I signaling in lung macrophages. In patients with severe COVID-19, lung macrophages expressed a robust inflammatory signature, which correlated with persistent IFN-I signaling at the single-cell level. Hence, we observed the uncoupling in the kinetics of the infiltration of pDCs in the lungs and the associated IFN-I signature, with the cytokine storm in macrophages. We observed that pDCs were the dominant IFN-α-producing cells in response to the virus in the blood, whereas macrophages produced IFN-α only when in physical contact with infected epithelial cells. We also showed that IFN-α produced by pDCs, after the sensing of SARS-CoV-2 by TLR7, mediated changes in macrophages at both transcriptional and epigenetic levels, which favored their hyperactivation by environmental stimuli. Together, these data indicate that the priming of macrophages can result from the response by pDCs to SARS-CoV-2, leading to macrophage activation in patients with severe COVID-19.
Collapse
Affiliation(s)
- Paôline Laurent
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
| | - Chao Yang
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
| | - André F. Rendeiro
- Institute for Computational Biomedicine and Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Benjamin E. Nilsson-Payant
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029, USA
- Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA
| | - Lucia Carrau
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029, USA
- Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA
| | - Vasuretha Chandar
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yaron Bram
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Benjamin R. tenOever
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10029, USA
- Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA
| | - Olivier Elemento
- Institute for Computational Biomedicine and Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA
- WorldQuant Initiative for Quantitative Prediction and Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10029, USA
- Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Lionel B. Ivashkiv
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
- Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Robert E. Schwartz
- Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Franck J. Barrat
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
- Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
| |
Collapse
|
|
13
|
Li Q, Li R, Yin H, Wang S, Liu B, Li J, Zhou M, Yan Q, Lu L. Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. Biomed Pharmacother 2022; 153:113459. [PMID: 36076574 PMCID: PMC9339262 DOI: 10.1016/j.biopha.2022.113459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.
Collapse
|
|
14
|
Faist A, Janowski J, Kumar S, Hinse S, Çalışkan DM, Lange J, Ludwig S, Brunotte L. Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond. Cells 2022; 11:2198. [PMID: 35883640 PMCID: PMC9316821 DOI: 10.3390/cells11142198] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/28/2022] [Accepted: 07/09/2022] [Indexed: 02/06/2023] Open
Abstract
Respiratory infections with newly emerging zoonotic viruses such as SARS-CoV-2, the etiological agent of COVID-19, often lead to the perturbation of the human innate and adaptive immune responses causing severe disease with high mortality. The responsible mechanisms are commonly virus-specific and often include either over-activated or delayed local interferon responses, which facilitate efficient viral replication in the primary target organ, systemic viral spread, and rapid onset of organ-specific and harmful inflammatory responses. Despite the distinct replication strategies, human infections with SARS-CoV-2 and highly pathogenic avian influenza viruses demonstrate remarkable similarities and differences regarding the mechanisms of immune induction, disease dynamics, as well as the long-term sequelae, which will be discussed in this review. In addition, we will highlight some important lessons about the effectiveness of antiviral and immunomodulatory therapeutic strategies that this pandemic has taught us.
Collapse
Affiliation(s)
- Aileen Faist
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- CiM-IMPRS, International Max Planck Research School—Molecular Biomedicine, Westfaelische Wilhelms-University Muenster, 48149 Muenster, Germany
| | - Josua Janowski
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- SP BioSciences Graduate Program, University of Muenster, 48149 Muenster, Germany
| | - Sriram Kumar
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- EvoPAD Research Training Group 2220, University of Muenster, 48149 Muenster, Germany
| | - Saskia Hinse
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
| | - Duygu Merve Çalışkan
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- EvoPAD Research Training Group 2220, University of Muenster, 48149 Muenster, Germany
| | - Julius Lange
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
| | - Stephan Ludwig
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- CiM-IMPRS, International Max Planck Research School—Molecular Biomedicine, Westfaelische Wilhelms-University Muenster, 48149 Muenster, Germany
- EvoPAD Research Training Group 2220, University of Muenster, 48149 Muenster, Germany
- Interdisciplinary Center for Clinical Research, University of Muenster, 48149 Muenster, Germany
| | - Linda Brunotte
- Institute of Virology, University of Muenster, 48149 Muenster, Germany; (A.F.); (J.J.); (S.K.); (S.H.); (D.M.Ç.); (J.L.); (S.L.)
- Interdisciplinary Center for Clinical Research, University of Muenster, 48149 Muenster, Germany
| |
Collapse
|
|
15
|
Recent advances in treatment Crimean-Congo hemorrhagic fever virus: A concise overview. Microb Pathog 2022; 169:105657. [PMID: 35753597 DOI: 10.1016/j.micpath.2022.105657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/19/2022] [Accepted: 06/22/2022] [Indexed: 11/22/2022]
Abstract
The Crimean Congo Hemorrhagic Fever Virus (CCHFV) is widespread in Africa, Asia, and Europe, among other places. The disease was initially discovered in the Crimean cities of the Soviet Union and the Congo, and it was given the name Crimean Congo because it induces hemorrhagic fever. According to studies, when the virus enters the body, it settles in immune cells such as macrophages and dendritic cells, causing them to malfunction and secrete inflammatory cytokines such as TNF-alpha, IL1, and IL6, resulting in cytokine storms that induces shock via endothelial activation and vascular leakage, while on the other hand, clots and disseminated intravascular coagulation (DIC) formation causes massive defects in various organs such as the liver and kidneys, as well as fatal bleeding. Disease prevention and treatment are crucial since no other effective vaccination against the disease has yet been developed. Immunotherapy is utilized as a consequence. One of the most effective treatments, when combined with compensatory therapies such as blood and platelet replacement, water, electrolytes, Fresh Frozen Plasma (FFP) replacement, and other compensatory therapies, is one of the most effective treatments. Studies; show that immunotherapy using IVIG and neutralizing and non-neutralizing monoclonal antibodies; cytokine therapy, and anti-inflammatory therapy using corticosteroids are effective ways to treat the disease.
Collapse
|
|
16
|
Luo S, Yang M, Zhao H, Han Y, Liu Y, Xiong X, Chen W, Li C, Sun L. Mitochondrial DNA-dependent inflammation in kidney diseases. Int Immunopharmacol 2022; 107:108637. [DOI: 10.1016/j.intimp.2022.108637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 11/15/2022]
|
|
17
|
Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther 2022; 7:113. [PMID: 35379777 PMCID: PMC8977435 DOI: 10.1038/s41392-022-00966-4] [Citation(s) in RCA: 318] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/21/2022] [Accepted: 03/15/2022] [Indexed: 12/11/2022] Open
Abstract
Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.
Collapse
|
|
18
|
Bastard P, Zhang Q, Zhang SY, Jouanguy E, Casanova JL. Type I interferons and SARS-CoV-2: from cells to organisms. Curr Opin Immunol 2022; 74:172-182. [PMID: 35149239 PMCID: PMC8786610 DOI: 10.1016/j.coi.2022.01.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 01/12/2022] [Accepted: 01/15/2022] [Indexed: 02/06/2023]
Abstract
Type I interferons (IFNs) have broad and potent antiviral activity. We review the interplay between type I IFNs and SARS-CoV-2. Human cells infected with SARS-CoV-2 in vitro produce low levels of type I IFNs, and SARS-CoV-2 proteins can inhibit various steps in type I IFN production and response. Exogenous type I IFNs inhibit viral growth in vitro. In various animal species infected in vivo, type I IFN deficiencies underlie higher viral loads and more severe disease than in control animals. The early administration of exogenous type I IFNs improves infection control. In humans, inborn errors of, and auto-antibodies against type I IFNs underlie life-threatening COVID-19 pneumonia. Overall, type I IFNs are essential for host defense against SARS-CoV-2 in individual cells and whole organisms.
Collapse
Affiliation(s)
- Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
| | - Qian Zhang
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Shen-Ying Zhang
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, NY, USA.
| |
Collapse
|
|
19
|
Nassar A, Ibrahim IM, Amin FG, Magdy M, Elgharib AM, Azzam EB, Nasser F, Yousry K, Shamkh IM, Mahdy SM, Elfiky AA. A Review of Human Coronaviruses' Receptors: The Host-Cell Targets for the Crown Bearing Viruses. Molecules 2021; 26:6455. [PMID: 34770863 PMCID: PMC8587140 DOI: 10.3390/molecules26216455] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/19/2022] Open
Abstract
A novel human coronavirus prompted considerable worry at the end of the year 2019. Now, it represents a significant global health and economic burden. The newly emerged coronavirus disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the primary reason for the COVID-19 global pandemic. According to recent global figures, COVID-19 has caused approximately 243.3 million illnesses and 4.9 million deaths. Several human cell receptors are involved in the virus identification of the host cells and entering them. Hence, understanding how the virus binds to host-cell receptors is crucial for developing antiviral treatments and vaccines. The current work aimed to determine the multiple host-cell receptors that bind with SARS-CoV-2 and other human coronaviruses for the purpose of cell entry. Extensive research is needed using neutralizing antibodies, natural chemicals, and therapeutic peptides to target those host-cell receptors in extremely susceptible individuals. More research is needed to map SARS-CoV-2 cell entry pathways in order to identify potential viral inhibitors.
Collapse
Affiliation(s)
- Aaya Nassar
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
| | - Ibrahim M. Ibrahim
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
| | - Fatma G. Amin
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
- Physics Department, Faculty of Science, Alexandria University, Alexandria 21519, Egypt
| | - Merna Magdy
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
| | - Ahmed M. Elgharib
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
| | - Eman B. Azzam
- Physics Department, Medical Biophysics Division, Faculty of Science, Helwan University, Cairo 11511, Egypt;
| | - Filopateer Nasser
- Biochemistry Department, Faculty of Science, Cairo University, Giza 12511, Egypt;
| | - Kirllos Yousry
- Faculty of Medicine, Cairo University, Cairo 11511, Egypt;
| | | | - Samah M. Mahdy
- National Museum of Egyptian Civilization, Ain Elsira-Elfustat, Cairo 11511, Egypt;
| | - Abdo A. Elfiky
- Biophysics Department, Faculty of Science, Cairo University, Giza 12511, Egypt; (I.M.I.); (F.G.A.); (M.M.); (A.M.E.)
| |
Collapse
|
|
20
|
Abstract
The innate immune response system forms an important line of defense by deploying a limited number of receptors specific for conserved microbial components. This deployment generates a rapid inflammatory response, while activating the adaptive immune system. Improvements in our understanding of the innate immune system have allowed us to explore various therapeutic strategies via modulation of the immune response.
Collapse
Affiliation(s)
- Bani Preet Kaur
- Detroit Medical Center, Children's Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201, USA.
| | - Elizabeth Secord
- Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, 3950 Beaubien Boulevard, Detroit, MI 48202, USA
| |
Collapse
|
|
21
|
Patel MV, Hopkins DC, Barr FD, Wira CR. Sex Hormones and Aging Modulate Interferon Lambda 1 Production and Signaling by Human Uterine Epithelial Cells and Fibroblasts. Front Immunol 2021; 12:718380. [PMID: 34630393 PMCID: PMC8497887 DOI: 10.3389/fimmu.2021.718380] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/12/2021] [Indexed: 11/30/2022] Open
Abstract
Estradiol (E2) and progesterone (P) have potent effects on immune function in the human uterine endometrium which is essential for creating an environment conducive for successful reproduction. Type III/lambda (λ) interferons (IFN) are implicated in immune defense of the placenta against viral pathogens, which occurs against the backdrop of high E2 and P levels. However, the effect of E2 and P in modulating the expression and function of IFNλ1 in the non-pregnant human uterine endometrium is unknown. We generated purified in vitro cultures of human uterine epithelial cells and stromal fibroblast cells recovered from hysterectomy specimens. Poly (I:C), a viral dsRNA mimic, potently increased secretion of IFNλ1 by both epithelial cells and fibroblasts. The secretion of IFNλ1 by epithelial cells significantly increased with increasing age following poly (I:C) stimulation. Stimulation of either cell type with E2 (5x10-8M) or P (1x10-7M) had no effect on expression or secretion of IFNλ1 either alone or in the presence of poly (I:C). E2 suppressed the IFNλ1-induced upregulation of the antiviral IFN-stimulated genes (ISGs) MxA, OAS2 and ISG15 in epithelial cells, but not fibroblasts. Estrogen receptor alpha (ERα) blockade using Raloxifene indicated that E2 mediated its inhibitory effects on ISG expression via ERα. In contrast to E2, P potentiated the upregulation of ISG15 in response to IFNλ1 but had no effect on MxA and OAS2 in epithelial cells. Our results demonstrate that the effects of E2 and P on IFNλ1-induced ISGs are cell-type specific. E2-mediated suppression, and selective P-mediated stimulation, of IFNλ1-induced ISG expression in uterine epithelial cells suggest that the effects of IFNλ1 varies with menstrual cycle stage, pregnancy, and menopausal status. The suppressive effect of E2 could be a potential mechanism by which ascending pathogens from the lower reproductive tract can infect the pregnant and non-pregnant endometrium.
Collapse
Affiliation(s)
- Mickey V. Patel
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
| | | | | | | |
Collapse
|
|
22
|
Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, Maglorius Renkilaraj MRL, Zhang P, Meertens L, Bolze A, Materna M, Korniotis S, Gervais A, Talouarn E, Bigio B, Seeleuthner Y, Bilguvar K, Zhang Y, Neehus AL, Ogishi M, Pelham SJ, Le Voyer T, Rosain J, Philippot Q, Soler-Palacín P, Colobran R, Martin-Nalda A, Rivière JG, Tandjaoui-Lambiotte Y, Chaïbi K, Shahrooei M, Darazam IA, Olyaei NA, Mansouri D, Hatipoğlu N, Palabiyik F, Ozcelik T, Novelli G, Novelli A, Casari G, Aiuti A, Carrera P, Bondesan S, Barzaghi F, Rovere-Querini P, Tresoldi C, Franco JL, Rojas J, Reyes LF, Bustos IG, Arias AA, Morelle G, Christèle K, Troya J, Planas-Serra L, Schlüter A, Gut M, Pujol A, Allende LM, Rodriguez-Gallego C, Flores C, Cabrera-Marante O, Pleguezuelo DE, de Diego RP, Keles S, Aytekin G, Akcan OM, Bryceson YT, Bergman P, Brodin P, Smole D, Smith CIE, Norlin AC, Campbell TM, Covill LE, Hammarström L, Pan-Hammarström Q, Abolhassani H, Mane S, Marr N, Ata M, Al Ali F, Khan T, Spaan AN, Dalgard CL, Bonfanti P, Biondi A, Tubiana S, Burdet C, Nussbaum R, Kahn-Kirby A, Snow AL, Bustamante J, Puel A, Boisson-Dupuis S, Zhang SY, Béziat V, Lifton RP, Bastard P, Notarangelo LD, Abel L, Su HC, Jouanguy E, Amara A, Soumelis V, Cobat A, Zhang Q, Casanova JL. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Sci Immunol 2021; 6:eabl4348. [PMID: 34413140 PMCID: PMC8532080 DOI: 10.1126/sciimmunol.abl4348] [Citation(s) in RCA: 283] [Impact Index Per Article: 70.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/12/2021] [Indexed: 01/16/2023]
Abstract
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
Collapse
Affiliation(s)
- Takaki Asano
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Fanny Onodi
- Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR7212, University of Paris, Research Institute of Saint-Louis, Saint-Louis Hospital, Paris, France
| | - Daniela Matuozzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Marcela Moncada-Velez
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Majistor Raj Luxman Maglorius Renkilaraj
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Peng Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Laurent Meertens
- Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR7212, University of Paris, Research Institute of Saint-Louis, Saint-Louis Hospital, Paris, France
| | | | - Marie Materna
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | | | - Adrian Gervais
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Estelle Talouarn
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Benedetta Bigio
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Yoann Seeleuthner
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Kaya Bilguvar
- Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Yu Zhang
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
- NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
| | - Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Simon J Pelham
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Tom Le Voyer
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Jérémie Rosain
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Quentin Philippot
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Pere Soler-Palacín
- Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia Spain
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain
- Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain
| | - Roger Colobran
- Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain
- Diagnostic Immunology Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain
- Immunology Division, Genetics Department, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain
| | - Andrea Martin-Nalda
- Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia Spain
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain
- Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain
| | - Jacques G Rivière
- Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia Spain
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Research Institute (VHIR), Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain
- Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain
| | - Yacine Tandjaoui-Lambiotte
- AP-HP, Avicenne Hospital, Intensive Care Unit, Bobigny, France
- INSERM U1272 Hypoxia & Lung, Bobigny, France
| | - Khalil Chaïbi
- Anesthesiology and Critical Care Medicine Department, APHP, Avicenne Hospital, Bobigny, France
- Common and Rare Kidney Diseases, Sorbonne University, INSERM UMR-S 1155, Paris, France
| | - Mohammad Shahrooei
- Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
- Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium
| | - Ilad Alavi Darazam
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Infectious Diseases and Tropical Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasrin Alipour Olyaei
- Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
- Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium
| | - Davood Mansouri
- Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran
| | - Nevin Hatipoğlu
- Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Figen Palabiyik
- Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Tayfun Ozcelik
- Department of Molecular Biology and Genetics, University of Bilkent, Bilkent-Ankara, Turkey
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, and Neuromed Institute, IRCCS, Pozzilli (IS), Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Giorgio Casari
- Vita-Salute San Raffaele University, Milan, Italy
- Clinical Genomics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Aiuti
- Vita-Salute San Raffaele University, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paola Carrera
- Clinical Genomics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Simone Bondesan
- Clinical Genomics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Barzaghi
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Patrizia Rovere-Querini
- Vita-Salute San Raffaele University, Milan, Italy
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Cristina Tresoldi
- Molecular Hematology Unit, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Jose Luis Franco
- Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
| | - Julian Rojas
- Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
| | | | | | - Andres Augusto Arias
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
- School of Microbiology, University of Antioquia UdeA, Medellín, Colombia
| | - Guillaume Morelle
- Department of General Pediatrics, Hôpital Bicêtre, AP-HP, University of Paris Saclay, Le Kremlin-Bicêtre, France
| | - Kyheng Christèle
- Department of General Pediatrics, Hôpital Bicêtre, AP-HP, University of Paris Saclay, Le Kremlin-Bicêtre, France
| | - Jesús Troya
- Department of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain
| | - Laura Planas-Serra
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain
| | - Agatha Schlüter
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain
| | - Marta Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028, Barcelona, Spain
| | - Aurora Pujol
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain
- Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Luis M Allende
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
- Complutense University, Madrid, Spain
| | - Carlos Rodriguez-Gallego
- Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain
- Department of Clinical Sciences, University of Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
| | - Carlos Flores
- Genomics Division, Institute of Technology and Renewable Energies (ITER), Santa Cruz de Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Health Institute of Carlos III, Madrid, Spain
- Research Unit, University Hospital of N.S. de Candelaria, Santa Cruz de Tenerife, Spain
- Institute of Biomedical technologies (ITB), University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Oscar Cabrera-Marante
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Daniel E Pleguezuelo
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Rebeca Pérez de Diego
- Institute of Biomedical Research of IdiPAZ, University Hospital "La Paz", Madrid, Spain
| | - Sevgi Keles
- Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey
| | - Gokhan Aytekin
- Konya City Hospital, Division of Allergy and Immunology, Konya, Turkey
| | - Ozge Metin Akcan
- Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey
| | - Yenan T Bryceson
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Peter Bergman
- Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Stockholm, Sweden
- The Immunodeficiency Unit, Infectious Disease Clinic, Karolinska University Hospital, Stockholm, Sweden
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institute, Solna, Sweden
| | - Daniel Smole
- Central Hospital-Anesthesia and Intensive Care Unit, Karlstad, Sweden
| | - C I Edvard Smith
- Department of Laboratory Medicine, Division of Biomolecular and Cellular Medicine, Karolinska Institute, Stockholm, Sweden
- The Immunodeficiency Unit, Infectious Disease Clinic, Karolinska University Hospital, Stockholm, Sweden
| | - Anna-Carin Norlin
- The Immunodeficiency Unit, Infectious Disease Clinic, Karolinska University Hospital, Stockholm, Sweden
| | - Tessa M Campbell
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Laura E Covill
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Lennart Hammarström
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | | | - Hassan Abolhassani
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shrikant Mane
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nico Marr
- Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar
| | - Manar Ata
- Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar
| | - Fatima Al Ali
- Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar
| | - Taushif Khan
- Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar
| | - András N Spaan
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Clifton L Dalgard
- Department of Anatomy, Physiology & Genetics Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Paolo Bonfanti
- Department of Infectious Diseases, San Gerardo Hospital-University of Milano-Bicocca, Monza, Italy
| | - Andrea Biondi
- Pediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM- Ospedale San Gerardo, Monza, Italy
| | - Sarah Tubiana
- Centre d'Investigation Clinique, INSERM CIC 1425, Paris, France
- Hôpital Bichat Claude Bernard, APHP, Paris, France
| | - Charles Burdet
- Centre d'Investigation Clinique, INSERM CIC 1425, Paris, France
- Université de Paris, IAME, INSERM UMR 1137, Paris, France
| | | | | | - Andrew L Snow
- Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Jacinta Bustamante
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
- Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France, EU
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Stéphanie Boisson-Dupuis
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Vivien Béziat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Richard P Lifton
- Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Luigi D Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
- NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
- NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Ali Amara
- Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR7212, University of Paris, Research Institute of Saint-Louis, Saint-Louis Hospital, Paris, France
| | - Vassili Soumelis
- University of Paris, INSERM U976, F-75006 Paris, France
- APHP, Hôpital Saint-Louis, Department of Immunology-Histocompatibility, 75010 Paris, France
| | - Aurélie Cobat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
- Howard Hughes Medical Institute, New York, NY, USA
| |
Collapse
|
|
23
|
Halouani A, Michaux H, Jmii H, Trussart C, Chahbi A, Martens H, Renard C, Aouni M, Hober D, Geenen V, Jaïdane H. Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus. Microorganisms 2021; 9:microorganisms9071537. [PMID: 34361972 PMCID: PMC8303261 DOI: 10.3390/microorganisms9071537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/10/2021] [Accepted: 07/16/2021] [Indexed: 01/09/2023] Open
Abstract
Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset.
Collapse
Affiliation(s)
- Aymen Halouani
- Laboratoire des Maladies Transmissibles et Substances Biologiquement Actives LR99ES27, Faculté de Pharmacie de Monastir, Université de Monastir, Monastir 5000, Tunisia; (A.H.); (H.J.); (M.A.)
- Faculté des Sciences de Tunis, Université de Tunis El Manar, Tunis 1068, Tunisia
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Hélène Michaux
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Habib Jmii
- Laboratoire des Maladies Transmissibles et Substances Biologiquement Actives LR99ES27, Faculté de Pharmacie de Monastir, Université de Monastir, Monastir 5000, Tunisia; (A.H.); (H.J.); (M.A.)
- Faculté des Sciences de Tunis, Université de Tunis El Manar, Tunis 1068, Tunisia
| | - Charlotte Trussart
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Ahlem Chahbi
- Laboratoire d’Hématologie, Faculté de Médecine de Tunis, Université de Tunis El Manar, Tunis 1007, Tunisia;
| | - Henri Martens
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Chantal Renard
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Mahjoub Aouni
- Laboratoire des Maladies Transmissibles et Substances Biologiquement Actives LR99ES27, Faculté de Pharmacie de Monastir, Université de Monastir, Monastir 5000, Tunisia; (A.H.); (H.J.); (M.A.)
| | - Didier Hober
- Laboratoire de Virologie EA3610, Faculté de Médecine, Université de Lille, CHU Lille, 59000 Lille, France;
| | - Vincent Geenen
- GIGA-I3 Immunoendocrinologie, Faculté de Médicine, Université de Liège, CHU-B34, Sart Tilman, 4000 Liège, Belgium; (H.M.); (C.T.); (H.M.); (C.R.); (V.G.)
| | - Hela Jaïdane
- Laboratoire des Maladies Transmissibles et Substances Biologiquement Actives LR99ES27, Faculté de Pharmacie de Monastir, Université de Monastir, Monastir 5000, Tunisia; (A.H.); (H.J.); (M.A.)
- Correspondence: ; Tel.: +216-98-677-174
| |
Collapse
|
|
24
|
Karnell JL, Wu Y, Mittereder N, Smith MA, Gunsior M, Yan L, Casey KA, Henault J, Riggs JM, Nicholson SM, Sanjuan MA, Vousden KA, Werth VP, Drappa J, Illei GG, Rees WA, Ratchford JN. Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Sci Transl Med 2021; 13:13/595/eabf8442. [PMID: 34039741 DOI: 10.1126/scitranslmed.abf8442] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 04/12/2021] [Indexed: 12/22/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced effector function, mediated rapid and potent depletion of pDCs through antibody-dependent cellular cytotoxicity. In cynomolgus monkeys, treatment with VIB7734 reduced pDCs in blood below the lower limit of normal by day 1 after the first dose. In two phase 1 studies in patients with autoimmune diseases, VIB7734 demonstrated an acceptable safety profile, comparable to that of placebo. In individuals with cutaneous lupus, VIB7734 profoundly reduced both circulating and tissue-resident pDCs, with a 97.6% median reduction in skin pDCs at study day 85 in VIB7734-treated participants. Reductions in pDCs in the skin correlated with a decrease in local type I IFN activity as well as improvements in clinical disease activity. Biomarker analysis suggests that responsiveness to pDC depletion therapy may be greater among individuals with high baseline type I IFN activity, supporting a central role for pDCs in type I IFN production in autoimmunity and further development of VIB7734 in IFN-associated diseases.
Collapse
Affiliation(s)
| | | | | | | | | | - Li Yan
- Viela Bio, Gaithersburg, MD 20878, USA
| | | | | | | | | | | | | | - Victoria P Werth
- Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | | | | | | |
Collapse
|
|
25
|
Kovachev SM. A Review on Inosine Pranobex Immunotherapy for Cervical HPV-Positive Patients. Infect Drug Resist 2021; 14:2039-2049. [PMID: 34103950 PMCID: PMC8180272 DOI: 10.2147/idr.s296709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/28/2021] [Indexed: 11/23/2022] Open
Abstract
The purpose of this review was to examine and summarize data for inosine pranobex (IP) immunotherapy in cervical HPV-positive patients. Persistent or recurring cervical human papillomavirus (HPV) infection is a major cause of cervical cancer. Self-clearance and blocking of cervical HPV infection depend on the status of the host immune system. Immunotherapy helps accelerate elimination of the infection. Host immunity is involved in the development of HPV infection. Several mechanisms of interaction between the virus and the immune system have been revealed; however, the mechanisms have not been completely elucidated. A properly functioning immune system impedes HPV progress and helps clear the pathogen from the body. IP has antiviral efficacy because it modulates both cellular and humoral immunities. IP has been on the market since 1971. Nevertheless, it has seldom been administered to treat cervical HPV infections. In this review, Google Scholar, PubMed/MEDLINE, Scopus, Cochrane Library, and Research Gate were searched for the period 1971–2021. Prospective controlled trials, observational and retrospective studies, and meta-analysis and reviews on immunotherapy against HPV cervical infection were explored. Prior studies showed strong clinical efficacy of combined and standalone IP therapy in reversing HPV-induced changes in the cervix, preventing disease progression, and clearing the pathogen. IP treatment enhanced host antiviral activity against HPV, delayed or stopped cervical oncogenesis, and rapidly removed HPV from the body.
Collapse
|
|
26
|
Verzosa AL, McGeever LA, Bhark SJ, Delgado T, Salazar N, Sanchez EL. Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms. Front Immunol 2021; 12:644664. [PMID: 34135889 PMCID: PMC8201405 DOI: 10.3389/fimmu.2021.644664] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
Alphaherpesviruses (α-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human α-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All α-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All α-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, α-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a life-long infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transported via sensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and non-neuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.
Collapse
Affiliation(s)
- Amanda L Verzosa
- Biology Department, College of Science and Engineering, San Francisco State University, San Francisco, CA, United States
| | - Lea A McGeever
- Biology Department, College of Science and Engineering, San Francisco State University, San Francisco, CA, United States
| | - Shun-Je Bhark
- Biology Department, Seattle Pacific University, Seattle, WA, United States
| | - Tracie Delgado
- Biology Department, Seattle Pacific University, Seattle, WA, United States
| | - Nicole Salazar
- Biology Department, College of Science and Engineering, San Francisco State University, San Francisco, CA, United States
| | - Erica L Sanchez
- Biology Department, College of Science and Engineering, San Francisco State University, San Francisco, CA, United States
| |
Collapse
|
|
27
|
Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection. Microorganisms 2021; 9:microorganisms9020402. [PMID: 33672010 PMCID: PMC7919294 DOI: 10.3390/microorganisms9020402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
Coxsackievirus B4 (CV-B4) can infect human and murine thymic epithelial cells (TECs). In a murine TEC cell line, CV-B4 can downregulate the transcription of the insulin-like growth factor 2 (Igf2) gene coding for the self-peptide of the insulin family. In this study, we show that CV-B4 infections of a murine TEC cell line decreased Igf2 P3 promoter activity by targeting a region near the transcription start site; however, the stability of Igf2 transcripts remained unchanged, indicating a regulation of Igf2 transcription. Furthermore, CV-B4 infections decreased STAT3 phosphorylation in vitro. We also showed that mice infected with CV-B4 had an altered expression of Igf2 isoforms as detected in TECs, followed by a decrease in the pro-IGF2 precursor in the thymus. Our study sheds new light on the intrathymic regulation of Igf2 transcription during CV-B4 infections and supports the hypothesis that a viral infection can disrupt central self-tolerance to insulin by decreasing Igf2 transcription in the thymic epithelium.
Collapse
|
|
28
|
Gadanec LK, McSweeney KR, Qaradakhi T, Ali B, Zulli A, Apostolopoulos V. Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells? Int J Mol Sci 2021; 22:992. [PMID: 33498183 PMCID: PMC7863934 DOI: 10.3390/ijms22030992] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/18/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.
Collapse
|
|
29
|
Jia A, James E, Lu HY, Sharma M, Modi BP, Biggs CM, Hildebrand KJ, Chomyn A, Erdle S, Kular H, Turvey SE. Clinical IRAK4 deficiency caused by homozygosity for the novel IRAK4 (c.1049delG, p.Gly350Glufs*15) variant. Cold Spring Harb Mol Case Stud 2020; 6:mcs.a005298. [PMID: 32532880 PMCID: PMC7304365 DOI: 10.1101/mcs.a005298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/15/2020] [Indexed: 11/25/2022] Open
Abstract
The innate immune system allows for rapid recognition of pathogens. Toll-like receptor (TLR) signaling is a key aspect of the innate immune response, and interleukin-1 receptor-associated kinase 4 (IRAK4) plays a vital role in the TLR signaling cascade. Each TLR recognizes a distinct set of pathogen-associated molecular patterns (PAMPs) that encompass conserved microbial components such as lipopolysaccharides and flagellin. Upon binding of PAMPs and TLR activation, TLR intracellular domains initiate the oligomerization of the myeloid differentiation primary response 88 (MyD88), IRAK1, IRAK2, and IRAK4 signaling platform known as the Myddosome complex while also triggering the Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway. The Myddosome complex initiates signal transduction pathways enabling the activation of NF-κB and mitogen-activated protein kinase (MAPK) transcription factors and the subsequent production of inflammatory cytokines. Human IRAK4 deficiency is an autosomal recessive inborn error of immunity that classically presents with blunted or delayed inflammatory response to infection and susceptibility to a narrow spectrum of pyogenic bacteria, particularly Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. We describe a case of IRAK4 deficiency in an 11-mo-old boy with concurrent S. pneumoniae bacteremia and S. aureus cervical lymphadenitis with a blunted inflammatory response to invasive infection. Although initial clinical immune profiling was unremarkable, a high degree of suspicion for an innate immune defect prompted genetic sequencing. Genetic testing revealed a novel variant in the IRAK4 gene (c.1049delG, p.(Gly350Glufs*15)) predicted to be likely pathogenic. Functional testing showed a loss of IRAK4 protein expression and abolished TLR signaling, confirming the pathogenicity of this novel IRAK4 variant.
Collapse
Affiliation(s)
- Alicia Jia
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada.,Department of Microbiology and Immunology, Vancouver, British Columbia V5Z 4H4, Canada
| | - Elliot James
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Henry Y Lu
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada.,Experimental Medicine Program, Faculty of Medicine, Vancouver, British Columbia V5Z 4H4, Canada
| | - Mehul Sharma
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada.,Experimental Medicine Program, Faculty of Medicine, Vancouver, British Columbia V5Z 4H4, Canada
| | - Bhavi P Modi
- Department of Medical Genetics, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
| | - Catherine M Biggs
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Kyla J Hildebrand
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Alanna Chomyn
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Stephanie Erdle
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Hasandeep Kular
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada
| | - Stuart E Turvey
- Division of Allergy and Clinical Immunology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia V5Z 4H4, Canada.,Department of Microbiology and Immunology, Vancouver, British Columbia V5Z 4H4, Canada
| |
Collapse
|
|
30
|
Hsieh MY, Lin JJ, Hsia SH, Huang JL, Yeh KW, Chang KW, Lee WI. Diminished toll-like receptor response in febrile infection-related epilepsy syndrome (FIRES). Biomed J 2020; 43:293-304. [PMID: 32651134 PMCID: PMC7424096 DOI: 10.1016/j.bj.2020.05.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 05/03/2020] [Accepted: 05/03/2020] [Indexed: 11/06/2022] Open
Abstract
Background Defective human TLR3 signaling causes recurrent and refractory herpes simplex encephalitis/encephalopathy. Children with febrile infection-related epilepsy syndrome with refractory seizures may have defective TLR responses. Methods Children with febrile infection-related epilepsy syndrome were enrolled in this study to evaluate TLR1-9 responses (IL-6, IL-8, IL-12p40, INF-α, INF-γ, and TNF-α) in their peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs), compared to those with febrile seizures and non-refractory epilepsy with/without underlying encephalitis/encephalopathy. Results Adenovirus and enterovirus were found in throat cultures of enrolled patients (2–13 years) as well as serologic IgM elevation of mycoplasma pneumonia and herpes simplex virus, although neither detectable pathogens nor anti-neural autoantibodies in the CSF could be noted. Their PBMCs and MDDCs trended to have impaired TLR responses and significantly lower in cytokine profiles of TLR3, TLR4, TLR7/8, and TLR9 responses but not other TLRs despite normal TLR expressions and normal candidate genes for defective TLR3 signaling. They also had decreased naïve T and T regulatory cells, and weakened phagocytosis. Conclusion Children with febrile infection-related epilepsy syndrome (FIRES) could have impaired TLR3, TLR4, TLR7/8, and TLR9 responses possibly relating to their weakened phagocytosis and decreased T regulatory cells.
Collapse
Affiliation(s)
- Meng-Ying Hsieh
- Division of Pediatrics, Chang Gung Memorial Hospital at Taipei, Taipei, Taiwan; Division of Pediatric Neurology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Jainn-Jim Lin
- Division of Pediatric Critical Care, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shao-Hsuan Hsia
- Division of Pediatric Critical Care, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Long Huang
- Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuo-Wei Yeh
- Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuei-Wen Chang
- Division of Pediatrics, Chang Gung Memorial Hospital at Taipei, Taipei, Taiwan; Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-I Lee
- Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| |
Collapse
|
|
31
|
Wiese MD, Manning-Bennett AT, Abuhelwa AY. Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 2020; 29:475-482. [PMID: 32255710 DOI: 10.1080/13543784.2020.1752660] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that can lead to permanent disability and deformity. Despite current treatment modalities, many patients are still unable to reach remission. Interleukin-1 receptor-associated kinase 4 (IRAK-4) inhibitors are novel agents designed to suppress immune signaling pathways involved in inflammation and joint destruction in RA. Four IRAK-4 inhibitors have entered clinical trials. AREAS COVERED This review summarizes the current stage of development of IRAK-4 inhibitors in clinical trials, detailing their chemistry, pharmacokinetics, and therapeutic potential in the treatment of RA. PubMed, Embase and restricted Google searches were conducted using the term 'IRAK-4', and publicly accessible clinical trial databases were reviewed. EXPERT OPINION IRAK-4 inhibitors are an exciting therapeutic option in RA management because unlike other targeted disease-modifying agents, they target the innate immune system. The role of IRAK-4 as a key component of Toll/Interleukin-1 receptor signaling and its potential for a low rate of infectious complications is particularly exciting and this may facilitate their use in combination treatment. A key aspect of upcoming clinical trials will be the identification of biomarkers predictive of treatment efficacy, which will help to define if and how they will be used in the clinic.
Collapse
Affiliation(s)
- Michael D Wiese
- Clinical and Health Sciences, University of South Australia , Adelaide, Australia.,Health and Biomedical Innovation Group, University of South Australia , Adelaide, Australia
| | - Arkady T Manning-Bennett
- Clinical and Health Sciences, University of South Australia , Adelaide, Australia.,Health and Biomedical Innovation Group, University of South Australia , Adelaide, Australia
| | - Ahmad Y Abuhelwa
- Clinical and Health Sciences, University of South Australia , Adelaide, Australia.,Australian Centre for Precision Medicine, Cancer Research Institute, University of South Australia , Adelaide, Australia
| |
Collapse
|
|
32
|
Gerada C, Campbell TM, Kennedy JJ, McSharry BP, Steain M, Slobedman B, Abendroth A. Manipulation of the Innate Immune Response by Varicella Zoster Virus. Front Immunol 2020; 11:1. [PMID: 32038653 PMCID: PMC6992605 DOI: 10.3389/fimmu.2020.00001] [Citation(s) in RCA: 182] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/02/2020] [Indexed: 12/12/2022] Open
Abstract
Varicella zoster virus (VZV) is the causative agent of chickenpox (varicella) and shingles (herpes zoster). VZV and other members of the herpesvirus family are distinguished by their ability to establish a latent infection, with the potential to reactivate and spread virus to other susceptible individuals. This lifelong relationship continually subjects VZV to the host immune system and as such VZV has evolved a plethora of strategies to evade and manipulate the immune response. This review will focus on our current understanding of the innate anti-viral control mechanisms faced by VZV. We will also discuss the diverse array of strategies employed by VZV to regulate these innate immune responses and highlight new knowledge on the interactions between VZV and human innate immune cells.
Collapse
Affiliation(s)
- Chelsea Gerada
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Tessa M Campbell
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Jarrod J Kennedy
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Brian P McSharry
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Megan Steain
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Barry Slobedman
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Allison Abendroth
- Infectious Diseases and Immunology, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
33
|
Abstract
The innate immune response system forms an important line of defense by deploying a limited number of receptors specific for conserved microbial components. This deployment generates a rapid inflammatory response, while activating the adaptive immune system. Improvements in our understanding of the innate immune system have allowed us to explore various therapeutic strategies via modulation of the immune response.
Collapse
Affiliation(s)
- Bani Preet Kaur
- Detroit Medical Center, Children's Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201, USA.
| | - Elizabeth Secord
- Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, 3950 Beaubien Boulevard, Detroit, MI 48202, USA
| |
Collapse
|
|
34
|
Hossain FMA, Choi JY, Uyangaa E, Park SO, Eo SK. The Interplay between Host Immunity and Respiratory Viral Infection in Asthma Exacerbation. Immune Netw 2019; 19:e31. [PMID: 31720042 PMCID: PMC6829071 DOI: 10.4110/in.2019.19.e31] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 08/22/2019] [Accepted: 08/25/2019] [Indexed: 12/16/2022] Open
Abstract
Asthma is one of the most common and chronic diseases characterized by multidimensional immune responses along with poor prognosis and severity. The heterogeneous nature of asthma may be attributed to a complex interplay between risk factors (either intrinsic or extrinsic) and specific pathogens such as respiratory viruses, and even bacteria. The intrinsic risk factors are highly correlated with asthma exacerbation in host, which may be mediated via genetic polymorphisms, enhanced airway epithelial lysis, apoptosis, and exaggerated viral replication in infected cells, resulting in reduced innate immune response and concomitant reduction of interferon (types I, II, and III) synthesis. The canonical features of allergic asthma include strong Th2-related inflammation, sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), eosinophilia, enhanced levels of Th2 cytokines, goblet cell hyperplasia, airway hyper-responsiveness, and airway remodeling. However, the NSAID-resistant non-Th2 asthma shows a characteristic neutrophilic influx, Th1/Th17 or even mixed (Th17-Th2) immune response and concurrent cytokine streams. Moreover, inhaled corticosteroid-resistant asthma may be associated with multifactorial innate and adaptive responses. In this review, we will discuss the findings of various in vivo and ex vivo models to establish the critical heterogenic asthmatic etiologies, host-pathogen relationships, humoral and cell-mediated immune responses, and subsequent mechanisms underlying asthma exacerbation triggered by respiratory viral infections.
Collapse
Affiliation(s)
- Ferdaus Mohd Altaf Hossain
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea.,Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Jin Young Choi
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea
| | - Erdenebileg Uyangaa
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea
| | - Seong Ok Park
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea
| | - Seong Kug Eo
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Korea
| |
Collapse
|
|
35
|
Barrat FJ, Su L. A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection. J Exp Med 2019; 216:1974-1985. [PMID: 31420375 DOI: 10.1084/jem.20181359] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/19/2019] [Accepted: 07/31/2019] [Indexed: 12/14/2022] Open
Abstract
Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here.
Collapse
Affiliation(s)
- Franck J Barrat
- Autoimmunity and Inflammation Program, HSS Research Institute, Hospital for Special Surgery, New York, NY .,Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY
| | - Lishan Su
- The Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC
| |
Collapse
|
|
36
|
Majzoub K, Wrensch F, Baumert TF. The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans. Viruses 2019; 11:v11080758. [PMID: 31426357 PMCID: PMC6723221 DOI: 10.3390/v11080758] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/08/2019] [Accepted: 08/14/2019] [Indexed: 12/13/2022] Open
Abstract
Animal cells have evolved dedicated molecular systems for sensing and delivering a coordinated response to viral threats. Our understanding of these pathways is almost entirely defined by studies in humans or model organisms like mice, fruit flies and worms. However, new genomic and functional data from organisms such as sponges, anemones and mollusks are helping redefine our understanding of these immune systems and their evolution. In this review, we will discuss our current knowledge of the innate immune pathways involved in sensing, signaling and inducing genes to counter viral infections in vertebrate animals. We will then focus on some central conserved players of this response including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and cGAS-STING, attempting to put their evolution into perspective. To conclude, we will reflect on the arms race that exists between viruses and their animal hosts, illustrated by the dynamic evolution and diversification of innate immune pathways. These concepts are not only important to understand virus-host interactions in general but may also be relevant for the development of novel curative approaches against human disease.
Collapse
Affiliation(s)
- Karim Majzoub
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France.
| | - Florian Wrensch
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, 67000 Strasbourg, France.
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
- Institut Universitaire de France, 75231 Paris, France.
| |
Collapse
|
|
37
|
Mei XF, Shi W, Zhang YY, Zhu B, Wang YR, Hou LJ, Zhao WP, Li J, Wang DY, Luo HL, Huang WY. DNA methylation and hydroxymethylation profiles reveal possible role of highly methylated TLR signaling on Fasciola gigantica excretory/secretory products (FgESPs) modulation of buffalo dendritic cells. Parasit Vectors 2019; 12:358. [PMID: 31337442 PMCID: PMC6647289 DOI: 10.1186/s13071-019-3615-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 07/13/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Excretory/secretory products (ESPs) released by parasites influence the development and functions of host dendritic cells (DCs). However, little is known about changes of DNA (hydroxy)methylation on DC development during Fasciola gigantica infection. The present study aimed to investigate whether F. gigantica ESPs (FgESPs) affects the development and functions of buffalo DCs through altering the DNA (hydroxy)methylation of DCs. METHODS Buffalo DCs were prepared from peripheral blood mononuclear cells (PBMCs) and characterized using scanning and transmission electron microscopy (SEM/TEM) and quantitative reverse transcriptional PCR (qRT-RCR). DCs were treated with 200 μg/ml of FgESPs in vitro, following DNA extraction. The DNA methylome and hydroxymethylome were profiled based on (hydroxy)methylated DNA immunoprecipitation sequencing [(h)MeDIP-Seq] and bioinformatics analyses. qRT-RCR was also performed to assess the gene transcription levels of interest. RESULTS FgESPs markedly suppressed DC maturation evidenced by morphological changes and downregulated gene expression of CD1a and MHC II. Totals of 5432 and 360 genes with significant changes in the 5-methylcytosine (5-mC) and the 5-hydroxymethylcytosine (5-hmC) levels, respectively, were identified in buffalo DCs in response to FgESPs challenge. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these differentially expressed genes were highly enriched in pathways associated with immune response. Some cancer-related pathways were also indicated. There were 111 genes demonstrating changes in both 5-mC and 5-hmC levels, 12 of which were interconnected and enriched in 12 pathways. The transcription of hypermethylated genes TLR2, TLR4 and IL-12B were downregulated or in a decreasing trend, while the mRNA level of high-hydroxymethylated TNF gene was upregulated in buffalo DCs post-exposure to FgESPs in vitro. CONCLUSIONS To our knowledge, the present study provides for the first time a unique genome-wide profile of DNA (hydroxy)methylation for DCs that interact with FgESPs, and suggests a possible mechanism of FgESPs in suppressing DC maturation and functions that are involved in TLR signaling.
Collapse
Affiliation(s)
- Xue-Fang Mei
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Wei Shi
- School of Preclinical Medicine, Guangxi Medical University, Nanning, People's Republic of China
| | - Yao-Yao Zhang
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Bin Zhu
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Yu-Rui Wang
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Lin-Jing Hou
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Wen-Ping Zhao
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China
| | - Jian Li
- State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, People's Republic of China
| | - Dong-Ying Wang
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China.
| | - Hong-Lin Luo
- Guangxi Key Laboratory for Aquatic Genetic Breeding and Healthy Aquaculture, Guangxi Institute of Fishery Sciences, Nanning, People's Republic of China.
| | - Wei-Yi Huang
- School of Animal Science and Technology, Guangxi University, Nanning, People's Republic of China.
| |
Collapse
|
|
38
|
Zhao W, Li D, Su Y, Zhao H, Pang W, Sun Y, Wu S. MicroRNA-147 negatively regulates expression of toll-like receptor-7 in rat macrophages and attenuates pristane induced rheumatoid arthritis in rats. Am J Transl Res 2019; 11:2219-2231. [PMID: 31105830 PMCID: PMC6511793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/01/2019] [Indexed: 06/09/2023]
Abstract
UNLABELLED Background/Introduction: Aberrant expression of Toll like receptors (TLR) plays a vital role in pathogenesis of rheumatoid arthritis (RA). Micro RNAs (miRs) could play important role in the related signaling pathways. The present study was undertaken to establish the link between miR-147 and TLR-7 in rat macrophages (in vitro) and in pristane (PS) induced arthritic rats. METHODOLOGY Dual luciferase assay was done to confirm the interaction between miR-147 and TLR-7. The effect of miR-147 on regulation of TLR-7 was done by RT-qPCR and Immunoblotting studies in rat macrophages (ATCC® CRL-2192TM) after treating them with miR-147 mimics and inhibitors. R-848 (Imiquimod) was used as TLR-7 stimulant, the mRNA and protein expression levels of IFN-β and TNF-α were recorded to determine the regulation of TLR-7. The levels of miR-147 and TLR-7 were evaluated during induction of rat bone marrow derived macrophage in the PS induced rat macrophages and spleens of methotrexate exposed rats. The miR-147 mimics was injected intraperitoneal to the PS treated rats and the severity of arthritis was studied. RESULTS The study confirmed TLR-7 mRNA as the potential target of miR-147 in rats. Alterations in miR-147 by transfecting mimics or inhibitors in ATCC® CRL-2192TM cells exhibited suppression and amelioration of TLR-7 and cytokine expression. The alteration in expression of miR-147 was inversely correlated with expression of TLR-7 during bone marrow derived macrophages induction in PS exposed cells and spleens. The abnormal expression was reversed in spleens of methotrexate treated arthritic rats. The treatment of miR-147 mimic caused suppression in expression of TLR-7 and improved the severity of arthritis in PS induced arthritic rats. CONCLUSIONS MiR-147 inversely regulates the TLR-7 signaling by targeting TLR-7 itself both in vivo and in vitro. The study provides a novel approach for conditions involving abnormal TLR-7 expression in arthritis.
Collapse
Affiliation(s)
- Wei Zhao
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| | - Dai Li
- Department of Anesthesiology, Chang Hai Hospital, Naval Military Medical UniversityShanghai 200433, China
| | - Yuqiang Su
- Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| | - Haikang Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| | - Weiwei Pang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| | - Yang Sun
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| | - Shengjun Wu
- Department of Gynaecology, The Second Affiliated Hospital of Xi’an Medical UniversityXi’an 710038, Shaanxi, China
| |
Collapse
|
|
39
|
Greenig M. HERVs, immunity, and autoimmunity: understanding the connection. PeerJ 2019; 7:e6711. [PMID: 30984482 PMCID: PMC6452852 DOI: 10.7717/peerj.6711] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 02/28/2019] [Indexed: 12/30/2022] Open
Abstract
Since their discovery in the 1960s, further investigation into endogenous retroviruses (ERVs) has challenged the conventional view of viral sequences as exclusively parasitic elements. Once presumed to be a group of passive genetic relics, it is becoming increasingly clear that this view of ERVs, while generally accurate, is incorrect in many specific cases. Research has identified ERV genes that appear to be co-opted by their mammalian hosts, but the biological function of ERV elements in humans remains a controversial subject. One area that has attracted some attention in this domain is the role of co-opted ERV elements in mammalian immune systems. The relationship between ERVs and human autoimmune diseases has also been investigated, but has historically been treated as a separate topic. This review will summarize the current evidence concerning the phenotypic significance of ERVs, both in the healthy immune system and in manifestations of autoimmunity. Furthermore, it will evaluate the relationship between these fields of study, and propose previously-unexplored molecular mechanisms through which human endogenous retroviruses might contribute to certain autoimmune pathologies. Investigation into these novel mechanisms could further our understanding of the molecular basis of autoimmune disease, and may one day provide new targets for treatment.
Collapse
Affiliation(s)
- Matthew Greenig
- Department of Life Sciences, Imperial College London, London, United Kingdom
| |
Collapse
|
|
40
|
Wu C, Xu X, Zhi X, Jiang Z, Li Y, Xie X, Chen X, Hu C. Identification and functional characterization of IRAK-4 in grass carp (Ctenopharyngodon idellus). FISH & SHELLFISH IMMUNOLOGY 2019; 87:438-448. [PMID: 30685465 DOI: 10.1016/j.fsi.2019.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 01/11/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
IL-1R-associated kinase 4 (IRAK4), a central TIR signaling mediator in innate immunity, can initiate a cascade of signaling events and lead to induction of inflammatory target gene expression eventually. In the present study, we cloned and characterized an IRAK4 orthologue from grass carp (Ctenopharyngodon idella). The full length cDNA of CiIRAK4 was 2057 bp with an ORF of 1422 bp encoding a polypeptide of 472 amino acids. Multiple alignments showed that IRAK4s were highly conserved among different species. Phylogenetic tree analysis revealed that CiIRAK4 shared high homologous with zebra fish IRAK4. Expression analysis indicated that CiIRAK4 was widely expressed in all tested tissues. It was significantly up-regulated after treatment with poly I:C, especially obvious in liver and spleen. Also, CiIRAK4 could be induced by poly I:C and LPS in CIK cells. Fluorescence microscopy assays showed that CiIRAK4 localized in the cytoplasm. RNAi-mediated knockdown and overexpression assays indicated that CiIRAK4 might have little effect on NF-kappa B p65 translocation from cytoplasm to nucleus, indicating that CiIRAK4 was dispensable for activation of NF-kappa B p65. In addition, IRAK4 promoted IRF5 nuclear translocation, which has nothing to do with the interaction between IRAK4 and IRF5. It suggested that fish IRAK4 kinase regulated IRF5 activity through indirect ways.
Collapse
Affiliation(s)
- Chuxin Wu
- Yuzhang Normal University, Nanchang, 330103, China
| | - Xiaowen Xu
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Xiaoping Zhi
- Yuzhang Normal University, Nanchang, 330103, China
| | - Zeyin Jiang
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Yinping Li
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Xiaofen Xie
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Xingxing Chen
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Chengyu Hu
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China.
| |
Collapse
|
|
41
|
Marongiu L, Gornati L, Artuso I, Zanoni I, Granucci F. Below the surface: The inner lives of TLR4 and TLR9. J Leukoc Biol 2019; 106:147-160. [PMID: 30900780 PMCID: PMC6597292 DOI: 10.1002/jlb.3mir1218-483rr] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/07/2019] [Accepted: 03/07/2019] [Indexed: 12/12/2022] Open
Abstract
TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.
Collapse
Affiliation(s)
- Laura Marongiu
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Laura Gornati
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Irene Artuso
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Ivan Zanoni
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.,Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Francesca Granucci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| |
Collapse
|
|
42
|
Andreakos E, Zanoni I, Galani IE. Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control. Curr Opin Immunol 2019; 56:67-75. [PMID: 30399529 PMCID: PMC6541392 DOI: 10.1016/j.coi.2018.10.007] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 01/22/2023]
Abstract
Lambda interferons (IFNλs, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNλs engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non-redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNλs in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNλs come thus to light as dual function cytokines mediating antiviral immunity and damage control.
Collapse
Affiliation(s)
- Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece; Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London W2 1NY, United Kingdom.
| | - Ivan Zanoni
- Division of Gastroenterology, Boston Children's Hospital, Harvard University, Boston, MA 02115, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Ioanna E Galani
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| |
Collapse
|
|
43
|
Yuan X, Wu H, Bu H, Zhou J, Zhang H. Targeting the immunity protein kinases for immuno-oncology. Eur J Med Chem 2018; 163:413-427. [PMID: 30530193 DOI: 10.1016/j.ejmech.2018.11.072] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/27/2018] [Accepted: 11/29/2018] [Indexed: 01/09/2023]
Abstract
With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.
Collapse
Affiliation(s)
- Xinrui Yuan
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Hanshu Wu
- Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Hong Bu
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Jinpei Zhou
- Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
| | - Huibin Zhang
- Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
| |
Collapse
|
|
44
|
Human Metapneumovirus Small Hydrophobic Protein Inhibits Interferon Induction in Plasmacytoid Dendritic Cells. Viruses 2018; 10:v10060278. [PMID: 29789500 PMCID: PMC6024365 DOI: 10.3390/v10060278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 05/20/2018] [Accepted: 05/21/2018] [Indexed: 12/21/2022] Open
Abstract
Human metapneumovirus (hMPV), a leading cause of respiratory tract infections in infants, encodes a small hydrophobic (SH) protein of unknown function. Here we show that infection of plasmacytoid dendritic cells (pDCs) with a recombinant virus lacking SH expression (rhMPV-ΔSH) enhanced the secretion of type I interferons (IFNs), which required TLR7 and MyD88 expression. HMPV SH protein inhibited TLR7/MyD88/TRAF6 signaling leading to IFN gene transcription, identifying a novel mechanism by which paramyxovirus SH proteins modulate innate immune responses.
Collapse
|
|
45
|
Mohammed I, Said DG, Dua HS. Human antimicrobial peptides in ocular surface defense. Prog Retin Eye Res 2017; 61:1-22. [DOI: 10.1016/j.preteyeres.2017.03.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/22/2017] [Accepted: 03/27/2017] [Indexed: 01/17/2023]
|
|
46
|
Andreakos E, Salagianni M, Galani IE, Koltsida O. Interferon-λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract. Front Immunol 2017; 8:1232. [PMID: 29033947 PMCID: PMC5626824 DOI: 10.3389/fimmu.2017.01232] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 09/19/2017] [Indexed: 12/18/2022] Open
Abstract
Type III interferons (IFNs), also termed lambda IFNs (IFNλs) or interleukins-28/29, constitute a new addition to the IFN family. They are induced upon infection and are particularly abundant at barrier surfaces, such as the respiratory and gastrointestinal tracts. Although they signal through a unique heterodimeric receptor complex comprising IFNLR1 and IL10RB, they activate a downstream signaling pathway remarkably similar to that of type I IFNs and share many functions with them. Yet, they also have important differences which are only now starting to unfold. Here, we review the current literature implicating type III IFNs in the regulation of immunity and homeostasis in the respiratory tract. We survey the common and unique characteristics of type III IFNs in terms of expression patterns, cellular targets, and biological activities and discuss their emerging role in first line defenses against respiratory viral infections. We further explore their immune modulatory functions and their involvement in the regulation of inflammatory responses during chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Type III IFNs are, therefore, arising as front-line guardians of immune defenses in the respiratory tract, fine tuning inflammation, and as potential novel therapeutics for the treatment of diverse respiratory diseases, including influenza virus infection and asthma.
Collapse
Affiliation(s)
- Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Maria Salagianni
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioanna E Galani
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ourania Koltsida
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| |
Collapse
|
|
47
|
Qi Z, Sun B, Zhang Q, Meng F, Xu Q, Wei Y, Gao Q. Molecular cloning, structural modeling, and expression analysis of MyD88 and IRAK4 of golden pompano (Trachinotus ovatus). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2017; 74:19-24. [PMID: 28408332 DOI: 10.1016/j.dci.2017.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/05/2017] [Indexed: 06/07/2023]
Abstract
MyD88 and IRAK4 are important components of TLR signaling pathways. However, information about MyD88 and IRAK4 is vacant in golden pompano (Trachinotus ovatus), a marine teleost with great commercial value. Thus, in this study the full lengths of trMyD88 and trIRAK4 were cloned from golden pompano using RT-PCR and RACE-PCR methods. trMyD88 was 1213 bp in length, encoding a putative protein of 288 amino acids (aa), consisting of a 99 aa of death domain at its N-terminal and a 137 aa of the TIR domain at its C-terminal. trIRAK4 was 1606 bp in length, encoding a putative protein of 469 aa, including an N-terminal death domain and a central kinase domain, connected by a ProST domain. Other domains or aa residues needed for their functions were also identified in trMyD88 and trIRAK4. Physicochemical features and 3-D structures of trMyD88 and trIRAK4 were also analyzed. Quantitative real-time PCR revealed that the 2 genes were ubiquitously expressed in tissues from healthy pompano, especially highly in the spleen and head kidney, indicating their roles in the immune response. Further, trMyD88 and trIRAK4 were up-regulated at 12 h after the Vibrio alginilyticus and polyI:C challenge and continued to 48 h post challenge. Our results demonstrated that MyD88 and IRAK4 played important roles in the golden pompano innate immune system, providing the basis for further study of the signaling pathways that these 2 genes are involved in.
Collapse
Affiliation(s)
- Zhitao Qi
- College of Animal Sciences, Yangtze University, Jingzhou, Hubei Province, 434020, China; Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, Yancheng Institute of Technology, Yancheng, Jiangsu, 224051, China.
| | - Baobao Sun
- Guangxi Key Laboratory of Subtropical Bioresource Conservation and Utilization, Guangxi University, Nanning, Guangxi Autonomous Region 53004, China
| | - Qihuan Zhang
- College of Animal Sciences, Yangtze University, Jingzhou, Hubei Province, 434020, China; Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, Yancheng Institute of Technology, Yancheng, Jiangsu, 224051, China
| | - Fancui Meng
- Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China
| | - Qiaoqing Xu
- College of Animal Sciences, Yangtze University, Jingzhou, Hubei Province, 434020, China
| | - Youchuan Wei
- Guangxi Key Laboratory of Subtropical Bioresource Conservation and Utilization, Guangxi University, Nanning, Guangxi Autonomous Region 53004, China.
| | - Qian Gao
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China
| |
Collapse
|
|
48
|
Wang YZ, Li JL, Wang X, Zhang T, Ho WZ. (-)-Epigallocatechin-3-gallate enhances poly I:C-induced interferon-λ1 production and inhibits hepatitis C virus replication in hepatocytes. World J Gastroenterol 2017; 23:5895-5903. [PMID: 28932081 PMCID: PMC5583574 DOI: 10.3748/wjg.v23.i32.5895] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 03/30/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of (-)-epigallocatechin-3-gallate (EGCG) on polyinosinic-polycytidylic acid (poly I:C)-triggered intracellular innate immunity against hepatitis C virus (HCV) in hepatocytes. METHODS A cell culture model of HCV infection was generated by infecting a hepatoma cell line, Huh7, with HCV JFH-1 strain (JFH-1-Huh7). Poly I:C with a high molecular weight and EGCG were used to stimulate the JFH-1-Huh7 cells. Real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of intracellular mRNAs and of intracellular and extracellular HCV RNA. Enzyme-linked immunosorbent assay was used to evaluate the interferon (IFN)-λ1 protein level in the cell culture supernatant. Immunostaining was used to examine HCV core protein expression in Huh7 cells. RESULTS Our recent study showed that HCV replication could impair poly I:C-triggered intracellular innate immune responses in hepatocytes. In the current study, we showed that EGCG treatment significantly increased the poly I:C-induced expression of Toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and IFN-λ1 in JFH-1-Huh7 cells. In addition, supplementation with EGCG increased the poly I:C-mediated antiviral activity in JFH-1-Huh7 cells at the intracellular and extracellular HCV RNA and protein levels. Further investigation of the mechanisms showed that EGCG treatment significantly enhanced the poly I:C-induced expression of IFN-regulatory factor 9 and several antiviral IFN-stimulated genes, including ISG15, ISG56, myxovirus resistance A, and 2'-5'-oligoadenylate synthetase 1, which encode the key antiviral elements in the IFN signaling pathway. CONCLUSION Our observations provide experimental evidence that EGCG has the ability to enhance poly I:C-induced intracellular antiviral innate immunity against HCV replication in hepatocytes.
Collapse
Affiliation(s)
- Yi-Zhong Wang
- Department of Infectious Diseases, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200040, China
| | - Jie-Liang Li
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States
| | - Xu Wang
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States
| | - Ting Zhang
- Department of Infectious Diseases, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai 200040, China
| | - Wen-Zhe Ho
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States
| |
Collapse
|
|
49
|
Lee KL, Ambler CM, Anderson DR, Boscoe BP, Bree AG, Brodfuehrer JI, Chang JS, Choi C, Chung S, Curran KJ, Day JE, Dehnhardt CM, Dower K, Drozda SE, Frisbie RK, Gavrin LK, Goldberg JA, Han S, Hegen M, Hepworth D, Hope HR, Kamtekar S, Kilty IC, Lee A, Lin LL, Lovering FE, Lowe MD, Mathias JP, Morgan HM, Murphy EA, Papaioannou N, Patny A, Pierce BS, Rao VR, Saiah E, Samardjiev IJ, Samas BM, Shen MWH, Shin JH, Soutter HH, Strohbach JW, Symanowicz PT, Thomason JR, Trzupek JD, Vargas R, Vincent F, Yan J, Zapf CW, Wright SW. Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 2017; 60:5521-5542. [PMID: 28498658 DOI: 10.1021/acs.jmedchem.7b00231] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Heidi M Morgan
- Worldwide Medicinal Chemistry, Pfizer Inc. , 1070 Science Center Drive, San Diego, California 92121, United States
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Jiangli Yan
- Worldwide Medicinal Chemistry, Pfizer Inc. , 1070 Science Center Drive, San Diego, California 92121, United States
| | | | | |
Collapse
|
|
50
|
Cornaby C, Jafek JL, Birrell C, Mayhew V, Syndergaard L, Mella J, Cheney W, Poole BD. EBI2 expression in B lymphocytes is controlled by the Epstein-Barr virus transcription factor, BRRF1 (Na), during viral infection. J Gen Virol 2017; 98:435-446. [PMID: 27902324 DOI: 10.1099/jgv.0.000660] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Epstein-Barr virus-induced gene 2 (EBI2) is an important chemotactic receptor that is involved in proper B-cell T-cell interactions. Epstein-Barr virus (EBV) has been shown to upregulate this gene upon infection of cell lines, but the timing and mechanism of this upregulation, as well as its importance to EBV infection, remain unknown. This work investigated EBV's manipulation of EBI2 expression of primary naive B cells. EBV infection induces EBI2 expression resulting in elevated levels of EBI2 after 24 h until 7 days post-infection, followed by a dramatic decline (P=0.027). Increased EBI2 expression was not found in non-specifically stimulated B cells or when irradiated virus was used. The EBV lytic gene BRRF1 exhibited a similar expression pattern to EBI2 (R2=0.4622). BRRF1-deficient EBV could not induce EBI2. However, B cells transduced with BRRF1 showed elevated expression of EBI2 (P=0.042), a result that was not seen with transduction of a different EBV lytic transfection factor, BRLF1. Based on these results, we conclude that EBI2 expression is directly influenced by EBV infection and that BRRF1 is necessary and sufficient for EBI2 upregulation during infection.
Collapse
Affiliation(s)
- Caleb Cornaby
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Jillian L Jafek
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Cameron Birrell
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Vera Mayhew
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Lauren Syndergaard
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Jeffrey Mella
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Wesley Cheney
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Brian D Poole
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| |
Collapse
|