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Zhong LY, Xie C, Zhang LL, Yang YL, Liu YT, Zhao GX, Bu GL, Tian XS, Jiang ZY, Yuan BY, Li PL, Wu PH, Jia WH, Münz C, Gewurz BE, Zhong Q, Sun C, Zeng MS. Research landmarks on the 60th anniversary of Epstein-Barr virus. SCIENCE CHINA. LIFE SCIENCES 2025; 68:354-380. [PMID: 39505801 DOI: 10.1007/s11427-024-2766-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/15/2024] [Indexed: 11/08/2024]
Abstract
Epstein-Barr virus (EBV), the first human oncovirus discovered in 1964, has become a focal point in virology, immunology, and oncology because of its unique biological characteristics and significant role in human diseases. As we commemorate the 60th anniversary of EBV's discovery, it is an opportune moment to reflect on the major advancements in our understanding of this complex virus. In this review, we highlight key milestones in EBV research, including its virion structure and life cycle, interactions with the host immune system, association with EBV-associated diseases, and targeted intervention strategies.
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Affiliation(s)
- Lan-Yi Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chu Xie
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Le-Le Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yan-Lin Yang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yuan-Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ge-Xin Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Guo-Long Bu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xian-Shu Tian
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Zi-Ying Jiang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Bo-Yu Yuan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Peng-Lin Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Pei-Huang Wu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, 8092, Switzerland
| | - Benjamin E Gewurz
- Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA, 02115, USA
- Harvard Program in Virology, Boston, MA, 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
| | - Qian Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Cong Sun
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Luo Y, Wang LJ, Wang CL. Advancing the understanding and management of blastic plasmacytoid dendritic cell neoplasm: Insights from recent case studies. World J Clin Cases 2024; 12:6441-6446. [PMID: 39507120 PMCID: PMC11438698 DOI: 10.12998/wjcc.v12.i31.6441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/11/2024] Open
Abstract
We specifically discuss the mechanisms of the pathogenesis, diagnosis, and management of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare but aggressive haematologic malignancy characterized by frequent skin manifestations and systemic dissemination. The article enriches our understanding of BPDCN through detailed case reports showing the clinical, immunophenotypic, and histopathological features that are critical for diagnosing this disease. These cases highlight the essential role of pathologists in employing advanced immunophenotyping techniques to accurately identify the disease early in its course and guide treatment decisions. Furthermore, we explore the implications of these findings for management strategies, emphasizing the use of targeted therapies such as tagraxofusp and the potential of allogeneic haematopoietic stem cell transplantation in achieving remission. The editorial underscores the importance of interdisciplinary approaches in managing BPDCN, pointing towards a future where precision medicine could significantly improve patient outcomes.
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Affiliation(s)
- Yan Luo
- Department of Stomatology, The People's Hospital of Dadukou District, Chongqing 400084, China
| | - Li-Juan Wang
- Department of Pathology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Cheng-Long Wang
- Department of Pathology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
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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.
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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.
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Kotov DI, Lee OV, Fattinger SA, Langner CA, Guillen JV, Peters JM, Moon A, Burd EM, Witt KC, Stetson DB, Jaye DL, Bryson BD, Vance RE. Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis. Cell 2023; 186:5536-5553.e22. [PMID: 38029747 PMCID: PMC10757650 DOI: 10.1016/j.cell.2023.11.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 06/16/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023]
Abstract
Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.
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Affiliation(s)
- Dmitri I Kotov
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
| | - Ophelia V Lee
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Stefan A Fattinger
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Charlotte A Langner
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jaresley V Guillen
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Joshua M Peters
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Andres Moon
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
| | - Eileen M Burd
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
| | - Kristen C Witt
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Daniel B Stetson
- Department of Immunology, University of Washington, Seattle, WA 98195, USA
| | - David L Jaye
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
| | - Bryan D Bryson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Russell E Vance
- Division of Immunology and Molecular Medicine, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
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Zhang X, Liu L, Wang F, Li H, Fan J, Xie J, Jiao Y, Han Z, Ma D. Pathogenicity and innate immune responses induced by fowl adenovirus serotype 8b in specific pathogen-free chicken. Poult Sci 2023; 102:102846. [PMID: 37354616 PMCID: PMC10404781 DOI: 10.1016/j.psj.2023.102846] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/26/2023] Open
Abstract
Fowl adenovirus serotype 8b (FAdV-8b), as causative agent of inclusion body hepatitis (IBH), poses a great threat to the poultry industry. Considering the importance of innate immune response in host against viral infections, we investigated pathogenicity of a FAdV-8b strain HLJ/151129 in 1-mo-old specific pathogen-free (SPF) chickens and immune responses of host to FAdV-8b infection in this study. The results demonstrated that no obvious clinical signs were observed in infected birds. Neither mobility nor mortality was observed in both FAdV-8b infected and control chickens, as well. However, hepatic necrosis and a small amount of inflammatory cell infiltration were observed by pathological analysis. Viral load was detected in bursa of Fabricius, cecal tonsils, liver, heart, spleen, Harderian glands, and thymus. Virus shedding and viremia generated as early as 3 days postinfection (dpi) (9/10) and reached the peak at 7 dpi (10/10). In addition, the infected birds had developed FAdV-specific antibodies at 7 dpi, and the antibody titers reached the peak at 14 dpi. Furthermore, the results demonstrated that the mRNA expression levels of most of toll-like receptors (TLRs), most of avian β-defensins (AvBDs), and cytokines [interleukin (IL)-2, IL-6, and interferon (IFN)-γ], were significantly upregulated in most tissues at early phases of FAdV-8b infection, especially in liver and spleen. In contrast, FAdV-8b infection results in downregulation of TLR4, TLR5, and TLR21 expressions in some tissues of infected chickens. In addition, FAdV-8b infection upregulated myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) p65, and TIR-domain-containing adapter inducing interferon-β (TRIF) expression in some tissues, while decreased NF-κBp65 and TRIF in spleen at both 72 hpi and 21 dpi. Taken together, these results confirmed that FAdV-8b could replicate in all investigated tissues of infected birds, and then, result in production of FAdV-specific antibody titers. Meanwhile, the FAdV-8b infection induces strong innate immune responses at early stage in chickens, which may associate with the viral pathogenesis.
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Affiliation(s)
- Xiaona Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China; State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Liangliang Liu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China; State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Fangfang Wang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Huixin Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Jiahui Fan
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China; State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Jingjing Xie
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China; State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Yaru Jiao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China; State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Zongxi Han
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin 150069, PR China
| | - Deying Ma
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China.
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Clement M, Forbester JL, Marsden M, Sabberwal P, Sommerville MS, Wellington D, Dimonte S, Clare S, Harcourt K, Yin Z, Nobre L, Antrobus R, Jin B, Chen M, Makvandi-Nejad S, Lindborg JA, Strittmatter SM, Weekes MP, Stanton RJ, Dong T, Humphreys IR. IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses. Nat Commun 2022; 13:5294. [PMID: 36075894 PMCID: PMC9454482 DOI: 10.1038/s41467-022-32587-4] [Citation(s) in RCA: 13] [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: 08/23/2021] [Accepted: 08/08/2022] [Indexed: 11/20/2022] Open
Abstract
Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.
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Affiliation(s)
- M Clement
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - J L Forbester
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
| | - M Marsden
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - P Sabberwal
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - M S Sommerville
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - D Wellington
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
| | - S Dimonte
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - S Clare
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - K Harcourt
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - Z Yin
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
| | - L Nobre
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK
| | - R Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK
| | - B Jin
- Fourth Military Medical University, Xian, China
| | - M Chen
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, 06536, USA
| | - S Makvandi-Nejad
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
| | - J A Lindborg
- Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - S M Strittmatter
- Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - M P Weekes
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK
| | - R J Stanton
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK
| | - T Dong
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DS, UK
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
| | - I R Humphreys
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff, CF14 4XN, UK.
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Bodro M, Cervera C, Linares L, Suárez B, Llopis J, Sanclemente G, Casadó-Llombart S, Fernández-Ruiz M, Fariñas MC, Cantisan S, Montejo M, Cordero E, Oriol I, Marcos MA, Lozano F, Moreno A, GESITRA-IC/SEIMC/REIPI investigators. Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study. Front Immunol 2022; 13:897912. [PMID: 36016941 PMCID: PMC9397545 DOI: 10.3389/fimmu.2022.897912] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.
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Affiliation(s)
- Marta Bodro
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- *Correspondence: Marta Bodro,
| | - Carlos Cervera
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Laura Linares
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Belén Suárez
- Immunology Department, Biomedical Diagnostic Center, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jaume Llopis
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Gemma Sanclemente
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Sergi Casadó-Llombart
- Immunoreceptors of the Innate and Adaptive Sistems, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mario Fernández-Ruiz
- Hospital Universitario “12 de Octubre”, Instituto de Investigación Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - María Carmen Fariñas
- University Hospital “Marqués de Valdecilla”, Instituto de Investigación “Marqués de Valdecilla” (IDIVAL), University of Cantabria, Santander, Spain
| | - Sara Cantisan
- Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain
| | - Miguel Montejo
- Hospital Universitario Cruces, Barakaldo, Universidad del País Vasco, Bilbao, Spain
| | - Elisa Cordero
- Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Virgen del Rocío University Hospital, Seville, Spain
- Institute of Biomedicine of Seville (IBiS), Virgen del Rocío and Virgen Macarena University Hospitals/CSIC/University of Seville, Seville, Spain
- Department of Medicine, University of Seville, Seville, Spain
| | - Isabel Oriol
- University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
| | - María Angeles Marcos
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Francisco Lozano
- Immunology Department, Biomedical Diagnostic Center, Hospital Clínic de Barcelona, Barcelona, Spain
- Immunoreceptors of the Innate and Adaptive Sistems, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biomedicine Department, University of Barcelona, Barcelona, Spain
| | - Asunción Moreno
- Infectious Diseases Department, Hospital Clinic de Barcelona - Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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8
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Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Comput Struct Biotechnol J 2022; 20:4415-4436. [PMID: 36051878 PMCID: PMC9420432 DOI: 10.1016/j.csbj.2022.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 12/02/2022] Open
Abstract
Recognition of pathogen-derived nucleic acids by host cells is an effective host strategy to detect pathogenic invasion and trigger immune responses. In the context of pathogen-specific pharmacology, there is a growing interest in mapping the interactions between pathogen-derived nucleic acids and host proteins. Insight into the principles of the structural and immunological mechanisms underlying such interactions and their roles in host defense is necessary to guide therapeutic intervention. Here, we discuss the newest advances in studies of molecular interactions involving pathogen nucleic acids and host factors, including their drug design, molecular structure and specific patterns. We observed that two groups of nucleic acid recognizing molecules, Toll-like receptors (TLRs) and the cytoplasmic retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) form the backbone of host responses to pathogen nucleic acids, with additional support provided by absent in melanoma 2 (AIM2) and DNA-dependent activator of Interferons (IFNs)-regulatory factors (DAI) like cytosolic activity. We review the structural, immunological, and other biological aspects of these representative groups of molecules, especially in terms of their target specificity and affinity and challenges in leveraging host-pathogen protein-nucleic acid interactions (HP-PNI) in drug discovery.
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Affiliation(s)
- Anuja Jain
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Shikha Mittal
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173234, India
| | - Lokesh P. Tripathi
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
- Riken Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa, Japan
| | - Ruth Nussinov
- Computational Structural Biology Section, Basic Science Program, Frederick National, Laboratory for Cancer Research, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel
| | - Shandar Ahmad
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
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9
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Abstract
Upon infection, DNA viruses can be sensed by pattern recognition receptors (PRRs), leading to the activation of type I and III interferons to block infection. Therefore, viruses must inhibit these signaling pathways, avoid being detected, or both. Papillomavirus virions are trafficked from early endosomes to the Golgi apparatus and wait for the onset of mitosis to complete nuclear entry. This unique subcellular trafficking strategy avoids detection by cytoplasmic PRRs, a property that may contribute to the establishment of infection. However, as the capsid uncoats within acidic endosomal compartments, the viral DNA may be exposed to detection by Toll-like receptor 9 (TLR9). In this study, we characterized two new papillomaviruses from bats and used molecular archeology to demonstrate that their genomes altered their nucleotide compositions to avoid detection by TLR9, providing evidence that TLR9 acts as a PRR during papillomavirus infection. Furthermore, we showed that TLR9, like other components of the innate immune system, is under evolutionary selection in bats, providing the first direct evidence for coevolution between papillomaviruses and their hosts. Finally, we demonstrated that the cancer-associated human papillomaviruses show a reduction in CpG dinucleotides within a TLR9 recognition complex.
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10
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Sartorius R, Trovato M, Manco R, D'Apice L, De Berardinis P. Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines. NPJ Vaccines 2021; 6:127. [PMID: 34711839 PMCID: PMC8553822 DOI: 10.1038/s41541-021-00391-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are transmembrane proteins belonging to the family of pattern-recognition receptors. They function as sensors of invading pathogens through recognition of pathogen-associated molecular patterns. After their engagement by microbial ligands, TLRs trigger downstream signaling pathways that culminate into transcriptional upregulation of genes involved in immune defense. Here we provide an updated overview on members of the TLR family and we focus on their role in antiviral response. Understanding of innate sensing and signaling of viruses triggered by these receptors would provide useful knowledge to prompt the development of vaccines able to elicit effective and long-lasting immune responses. We describe the mechanisms developed by viral pathogens to escape from immune surveillance mediated by TLRs and finally discuss how TLR/virus interplay might be exploited to guide the design of innovative vaccine platforms.
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Affiliation(s)
- Rossella Sartorius
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
| | - Maria Trovato
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Roberta Manco
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Luciana D'Apice
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
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11
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Piersma SJ, Brizić I. Natural killer cell effector functions in antiviral defense. FEBS J 2021; 289:3982-3999. [PMID: 34125493 DOI: 10.1111/febs.16073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/27/2021] [Accepted: 06/14/2021] [Indexed: 11/27/2022]
Abstract
Natural killer (NK) cells are innate lymphoid cells involved in the control of tumors and viral infections. They provide protection by producing cytokines and by directly lysing target cells. Both effector mechanisms have been identified to contribute to viral control, depending on the context of infection. Activation of NK cells depends on the integration of signals received by cytokine receptors and activation and inhibitory receptors recognizing ligands expressed by virus-infected cells. While the control of viral infections by NK cells is well established, the signals perceived by NK cells and how these signals integrate to mediate optimal viral control have been focus of ongoing research. Here, we discuss the current knowledge on NK cell activation and integration of signals that lead to interferon gamma production and cytotoxicity in viral infections. We review NK cell interactions with viruses, with particular focus on murine cytomegalovirus studies, which helped elucidate crucial aspects of antiviral NK cell immunity.
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Affiliation(s)
- Sytse J Piersma
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Ilija Brizić
- Center for Proteomics, Faculty of Medicine, University of Rijeka, Croatia
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12
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Mulas F, Wang X, Song S, Nishanth G, Yi W, Brunn A, Larsen PK, Isermann B, Kalinke U, Barragan A, Naumann M, Deckert M, Schlüter D. The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13. Cell Mol Immunol 2021; 18:1512-1527. [PMID: 32024978 PMCID: PMC8167118 DOI: 10.1038/s41423-020-0362-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 01/01/2020] [Indexed: 01/09/2023] Open
Abstract
Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.
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Affiliation(s)
- Floriana Mulas
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Xu Wang
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany.
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany.
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
| | - Shanshan Song
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
| | - Gopala Nishanth
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Wenjing Yi
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Anna Brunn
- Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Pia-Katharina Larsen
- Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625, Hannover, Germany
| | - Berend Isermann
- Institute for Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625, Hannover, Germany
- Cluster of Excellence-Resolving Infection Susceptibility (RESIST), Hannover Medical School, 30625, Hannover, Germany
| | - Antonio Barragan
- Department of Molecular Biosciences, Stockholm University, 10691, Stockholm, Sweden
| | - Michael Naumann
- Institute for Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany
| | - Martina Deckert
- Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany.
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany.
- Cluster of Excellence-Resolving Infection Susceptibility (RESIST), Hannover Medical School, 30625, Hannover, Germany.
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13
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Yun TJ, Igarashi S, Zhao H, Perez OA, Pereira MR, Zorn E, Shen Y, Goodrum F, Rahman A, Sims PA, Farber DL, Reizis B. Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells. Sci Immunol 2021; 6:6/58/eabc7302. [PMID: 33811059 DOI: 10.1126/sciimmunol.abc7302] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 11/19/2020] [Accepted: 03/01/2021] [Indexed: 12/12/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.
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Affiliation(s)
- Tae Jin Yun
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Suzu Igarashi
- Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA
| | - Haoquan Zhao
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Oriana A Perez
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Marcus R Pereira
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Felicia Goodrum
- Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA
| | - Adeeb Rahman
- Precision Immunology Institute, Department of Genetics and Genomic Sciences, Tisch Cancer Institute, and Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Peter A Sims
- Department of Systems Biology, Department of Biochemistry & Molecular Biophysics, and Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Donna L Farber
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.,Department of Surgery and Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Boris Reizis
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
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14
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Murine cytomegaloviruses m139 targets DDX3 to curtail interferon production and promote viral replication. PLoS Pathog 2020; 16:e1008546. [PMID: 33031466 PMCID: PMC7575108 DOI: 10.1371/journal.ppat.1008546] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 10/20/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022] Open
Abstract
Cytomegaloviruses (CMV) infect many different cell types and tissues in their respective hosts. Monocytes and macrophages play an important role in CMV dissemination from the site of infection to target organs. Moreover, macrophages are specialized in pathogen sensing and respond to infection by secreting cytokines and interferons. In murine cytomegalovirus (MCMV), a model for human cytomegalovirus, several genes required for efficient replication in macrophages have been identified, but their specific functions remain poorly understood. Here we show that MCMV m139, a gene of the conserved US22 gene family, encodes a protein that interacts with the DEAD box helicase DDX3, a protein involved in pathogen sensing and interferon (IFN) induction, and the E3 ubiquitin ligase UBR5. DDX3 and UBR5 also participate in the transcription, processing, and translation of a subset of cellular mRNAs. We show that m139 inhibits DDX3-mediated IFN-α and IFN-β induction and is necessary for efficient viral replication in bone-marrow derived macrophages. In vivo, m139 is crucial for viral dissemination to local lymph nodes and to the salivary glands. An m139-deficient MCMV also replicated to lower titers in SVEC4-10 endothelial cells. This replication defect was not accompanied by increased IFN-β transcription, but was rescued by knockout of either DDX3 or UBR5. Moreover, m139 co-localized with DDX3 and UBR5 in viral replication compartments in the cell nucleus. These results suggest that m139 inhibits DDX3-mediated IFN production in macrophages and antagonizes DDX3 and UBR5-dependent functions related to RNA metabolism in endothelial cells. Human cytomegalovirus is an opportunistic pathogen that causes severe infections in immunocompromised individuals. The virus infects certain cell types, such as macrophages and endothelial cells, to ensure its dissemination within the body. Little is known about the viral factors that promote a productive infection of these cell types. The identification of critical viral factors and the molecular pathways they target can lead to the development of novel antiviral treatment strategies. Using the mouse cytomegalovirus as a model, we studied the viral m139 gene, which is important for virus replication in macrophages and endothelial cells and for dissemination in the mouse. This gene encodes a protein that interacts with the host proteins DDX3 and UBR5. Both proteins are involved in gene expression, and the RNA helicase DDX3 also participates in mounting an innate antiviral response. By interacting with DDX3 and UBR5, m139 ensures efficient viral replication in endothelial cells. Importantly, we identify m139 as a new viral DDX3 inhibitor, which curtails the production of interferon by macrophages.
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15
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Piersma SJ, Poursine-Laurent J, Yang L, Barber GN, Parikh BA, Yokoyama WM. Virus infection is controlled by hematopoietic and stromal cell sensing of murine cytomegalovirus through STING. eLife 2020; 9:56882. [PMID: 32723479 PMCID: PMC7413665 DOI: 10.7554/elife.56882] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/27/2020] [Indexed: 12/28/2022] Open
Abstract
Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal cells. Infected splenic stromal cells produced IFN-I in a cGAS-STING-dependent and MyD88-independent manner, while we confirmed plasmacytoid dendritic cell IFN-I had inverse requirements. MCMV-induced natural killer cytotoxicity was dependent on MyD88 and STING. Thus, MyD88 and STING contribute to MCMV control in distinct cell types that initiate downstream immune responses.
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Affiliation(s)
- Sytse J Piersma
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States
| | - Jennifer Poursine-Laurent
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States
| | - Liping Yang
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States
| | - Glen N Barber
- Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, United States
| | - Bijal A Parikh
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
| | - Wayne M Yokoyama
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, United States
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16
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Audiger C, Fois A, Thomas AL, Janssen E, Pelletier M, Lesage S. Merocytic Dendritic Cells Compose a Conventional Dendritic Cell Subset with Low Metabolic Activity. THE JOURNAL OF IMMUNOLOGY 2020; 205:121-132. [PMID: 32461238 DOI: 10.4049/jimmunol.1900970] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 04/29/2020] [Indexed: 12/14/2022]
Abstract
Conventional dendritic cells (cDCs) are arguably the most potent APCs that induce the activation of naive T cells in response to pathogens. In addition, at steady-state, cDCs help maintain immune tolerance. Two subsets of cDCs have been extensively characterized, namely cDC1 and cDC2, each contributing differently to immune responses. Recently, another dendritic cell (DC) subset, termed merocytic DCs (mcDCs), was defined. In contrast to both cDC1 and cDC2, mcDCs reverse T cell anergy, properties that could be exploited to potentiate cancer treatments. Yet, whether mcDCs represent an unconventional DC or a cDC subset remains to be defined. In this article, we further characterize mcDCs and find that they bear true characteristics of cDC subsets. Indeed, as for cDCs, mcDCs express the cDC-restricted transcription factor Zbtb46 and display very potent APC activity. In addition, mcDC population dynamics parallels that of cDC1 and cDC2 in both reconstitution kinetic studies and parabiotic mice. We next investigated their relatedness to cDC1 and cDC2 and demonstrate that mcDCs are not dependent on cDC1-related Irf8 and Batf3 transcription factors, are dependent on Irf4, a cDC2-specific transcription factor, and express a unique transcriptomic signature. Finally, we find that cDC1, cDC2, and mcDCs all present with different metabolic phenotypes, in which mcDCs exhibit the lowest glucose uptake activity and mcDC survival is the least affected by glycolysis inhibition. Defining the properties of mcDCs in mice may help identify a functionally equivalent subset in humans leading to the development of innovative cancer immunotherapies.
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Affiliation(s)
- Cindy Audiger
- Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Adrien Fois
- Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Alyssa L Thomas
- Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229.,Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Edith Janssen
- Janssen Research and Development, Spring House, PA 19477
| | - Martin Pelletier
- Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.,Département de Microbiologie-Infectiologie et d'Immunologie, Université Laval, Quebec City, Quebec G1V 0A6, Canada
| | - Sylvie Lesage
- Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; .,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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17
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Carriere J, Rao Y, Liu Q, Lin X, Zhao J, Feng P. Post-translational Control of Innate Immune Signaling Pathways by Herpesviruses. Front Microbiol 2019; 10:2647. [PMID: 31798565 PMCID: PMC6868034 DOI: 10.3389/fmicb.2019.02647] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/30/2019] [Indexed: 12/21/2022] Open
Abstract
Herpesviruses constitute a large family of disease-causing DNA viruses. Each herpesvirus strain is capable of infecting particular organisms with a specific cell tropism. Upon infection, pattern recognition receptors (PRRs) recognize conserved viral features to trigger signaling cascades that culminate in the production of interferons and pro-inflammatory cytokines. To invoke a proper immune response while avoiding collateral tissue damage, signaling proteins involved in these cascades are tightly regulated by post-translational modifications (PTMs). Herpesviruses have developed strategies to subvert innate immune signaling pathways in order to ensure efficient viral replication and achieve persistent infection. The ability of these viruses to control the proteins involved in these signaling cascades post-translationally, either directly via virus-encoded enzymes or indirectly through the deregulation of cellular enzymes, has been widely reported. This ability provides herpesviruses with a powerful tool to shut off or restrict host antiviral and inflammatory responses. In this review, we highlight recent findings on the herpesvirus-mediated post-translational control along PRR-mediated signaling pathways.
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Affiliation(s)
| | | | | | | | | | - Pinghui Feng
- Section of Infection and Immunity, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, United States
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18
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Akilesh HM, Buechler MB, Duggan JM, Hahn WO, Matta B, Sun X, Gessay G, Whalen E, Mason M, Presnell SR, Elkon KB, Lacy-Hulbert A, Barnes BJ, Pepper M, Hamerman JA. Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes. Science 2019; 363:363/6423/eaao5213. [PMID: 30630901 DOI: 10.1126/science.aao5213] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 08/04/2018] [Accepted: 11/28/2018] [Indexed: 12/14/2022]
Abstract
Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.
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Affiliation(s)
- Holly M Akilesh
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA.,Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Matthew B Buechler
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA.,Department of Immunology, University of Washington, Seattle, WA, USA
| | - Jeffrey M Duggan
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA.,Department of Immunology, University of Washington, Seattle, WA, USA
| | - William O Hahn
- Department of Immunology, University of Washington, Seattle, WA, USA.,Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Bharati Matta
- Center for Autoimmune, Musculoskeletal and Hematopoietic Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA
| | - Xizhang Sun
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Griffin Gessay
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA
| | - Elizabeth Whalen
- Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA
| | - Michael Mason
- Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA
| | - Scott R Presnell
- Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA
| | - Keith B Elkon
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA.,Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Adam Lacy-Hulbert
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA.,Department of Immunology, University of Washington, Seattle, WA, USA
| | - Betsy J Barnes
- Center for Autoimmune, Musculoskeletal and Hematopoietic Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA
| | - Marion Pepper
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Jessica A Hamerman
- Immunology Program, Benaroya Research Institute, Seattle, WA, USA. .,Department of Immunology, University of Washington, Seattle, WA, USA
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19
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Epstein-Barr Virus and Innate Immunity: Friends or Foes? Microorganisms 2019; 7:microorganisms7060183. [PMID: 31238570 PMCID: PMC6617214 DOI: 10.3390/microorganisms7060183] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/20/2019] [Accepted: 06/22/2019] [Indexed: 12/16/2022] Open
Abstract
Epstein–Barr virus (EBV) successfully persists in the vast majority of adults but causes lymphoid and epithelial malignancies in a small fraction of latently infected individuals. Innate immunity is the first-line antiviral defense, which EBV has to evade in favor of its own replication and infection. EBV uses multiple strategies to perturb innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like, and AIM2-like receptors as well as cyclic GMP-AMP synthase. EBV also counteracts interferon production and signaling, including TBK1-IRF3 and JAK-STAT pathways. However, activation of innate immunity also triggers pro-inflammatory response and proteolytic cleavage of caspases, both of which exhibit proviral activity under some circumstances. Pathogenic inflammation also contributes to EBV oncogenesis. EBV activates NFκB signaling and induces pro-inflammatory cytokines. Through differential modulation of the proviral and antiviral roles of caspases and other host factors at different stages of infection, EBV usurps cellular programs for death and inflammation to its own benefits. The outcome of EBV infection is governed by a delicate interplay between innate immunity and EBV. A better understanding of this interplay will instruct prevention and intervention of EBV-associated cancers.
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20
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Adams NM, Sun JC. Spatial and temporal coordination of antiviral responses by group 1 ILCs. Immunol Rev 2019; 286:23-36. [PMID: 30294970 DOI: 10.1111/imr.12710] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/10/2018] [Indexed: 12/20/2022]
Abstract
Group 1 innate lymphocytes consist of a phenotypically, spatially, and functionally heterogeneous population of NK cells and ILC1s that are engaged during pathogen invasion. We are only beginning to understand the context-dependent roles that different subsets of group 1 innate lymphocytes play during homeostatic perturbations. With a focus on viral infection, this review highlights the organization and regulation of spatially and temporally distinct waves of NK cell and ILC1 responses that collectively serve to achieve optimal viral control.
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Affiliation(s)
- Nicholas M Adams
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York.,Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York.,Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York.,Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York
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21
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Butterfield JS, Biswas M, Shirley JL, Kumar SR, Sherman A, Terhorst C, Ling C, Herzog RW. TLR9-Activating CpG-B ODN but Not TLR7 Agonists Triggers Antibody Formation to Factor IX in Muscle Gene Transfer. Hum Gene Ther Methods 2019; 30:81-92. [PMID: 31140323 PMCID: PMC6590725 DOI: 10.1089/hgtb.2019.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023] Open
Abstract
Innate immune signals that promote B cell responses in gene transfer are generally ill-defined. In this study, we evaluate the effect of activating endosomal Toll-like receptors 7, 8, and 9 (TLR7, TLR7/8, and TLR9) on antibody formation during muscle-directed gene therapy with adeno-associated virus (AAV) vectors. We examined whether activation of endosomal TLRs, by adenine analog CL264 (TLR7 agonist), imidazolquinolone compound R848 (TLR7/8 agonist), or class B CpG oligodeoxynucleotides ODN1826 (TLR9 agonist), could augment antibody formation upon intramuscular administration of AAV1 expressing human clotting factor IX (AAV1-hFIX) in mice. The TLR9 agonist robustly enhanced antibody formation by the 1st week, thus initially eliminating systemic hFIX expression. By contrast, the TLR7 and TLR7/8 agonists did not markedly promote antibody formation, or significantly reduce circulating hFIX. We concurrently investigated the effects of these TLR agonists during muscle gene transfer on mature B cells and dendritic cells (DCs) in the draining lymph nodes including conventional DCs (CD11b+ or CD8α+ cDCs), monocyte-derived dendritic cells (moDCs), and plasmacytoid dendritic cells (pDCs). Only TLR9 stimulation caused a striking increase in the frequency of moDCs within 24 h. The TLR7/8 and TLR9 agonists activated pDCs, both subsets of cDCs, and mature B cells, whereas the TLR7 agonist had only mild effects on these cells. Thus, these TLR ligands have distinct effects on DCs and mature B cells, yet only the TLR9 agonist enhanced the humoral immune response against AAV-expressed hFIX. These new findings indicate a unique ability of certain TLR9 agonists to stimulate B cell responses in muscle gene transfer through enrichment of moDCs.
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Affiliation(s)
| | - Moanaro Biswas
- Department of Pediatrics, University of Florida, Gainesville, Florida
- Department of Pediatrics, Indiana University, Indianapolis, Indiana
| | - Jamie L. Shirley
- Department of Pediatrics, University of Florida, Gainesville, Florida
| | - Sandeep R.P. Kumar
- Department of Pediatrics, Indiana University, Indianapolis, Indiana
- Herman B Wells Center for Pediatric Research, IAPUI, Indianapolis, Indiana
| | - Alexandra Sherman
- Department of Pediatrics, Indiana University, Indianapolis, Indiana
- Herman B Wells Center for Pediatric Research, IAPUI, Indianapolis, Indiana
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts
| | - Chen Ling
- Department of Pediatrics, University of Florida, Gainesville, Florida
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Roland W. Herzog
- Department of Pediatrics, University of Florida, Gainesville, Florida
- Department of Pediatrics, Indiana University, Indianapolis, Indiana
- Herman B Wells Center for Pediatric Research, IAPUI, Indianapolis, Indiana
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22
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Ali S, Mann-Nüttel R, Schulze A, Richter L, Alferink J, Scheu S. Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver's Seat. Front Immunol 2019; 10:778. [PMID: 31031767 PMCID: PMC6473462 DOI: 10.3389/fimmu.2019.00778] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 03/25/2019] [Indexed: 12/28/2022] Open
Abstract
Type I Interferons (IFNs) are hallmark cytokines produced in immune responses to all classes of pathogens. Type I IFNs can influence dendritic cell (DC) activation, maturation, migration, and survival, but also directly enhance natural killer (NK) and T/B cell activity, thus orchestrating various innate and adaptive immune effector functions. Therefore, type I IFNs have long been considered essential in the host defense against virus infections. More recently, it has become clear that depending on the type of virus and the course of infection, production of type I IFN can also lead to immunopathology or immunosuppression. Similarly, in bacterial infections type I IFN production is often associated with detrimental effects for the host. Although most cells in the body are thought to be able to produce type I IFN, plasmacytoid DCs (pDCs) have been termed the natural "IFN producing cells" due to their unique molecular adaptations to nucleic acid sensing and ability to produce high amounts of type I IFN. Findings from mouse reporter strains and depletion experiments in in vivo infection models have brought new insights and established that the role of pDCs in type I IFN production in vivo is less important than assumed. Production of type I IFN, especially the early synthesized IFNβ, is rather realized by a variety of cell types and cannot be mainly attributed to pDCs. Indeed, the cell populations responsible for type I IFN production vary with the type of pathogen, its tissue tropism, and the route of infection. In this review, we summarize recent findings from in vivo models on the cellular source of type I IFN in different infectious settings, ranging from virus, bacteria, and fungi to eukaryotic parasites. The implications from these findings for the development of new vaccination and therapeutic designs targeting the respectively defined cell types are discussed.
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Affiliation(s)
- Shafaqat Ali
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
- Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
| | - Ritu Mann-Nüttel
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Anja Schulze
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Lisa Richter
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Judith Alferink
- Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
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23
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Stojanovic B, Milovanovic J, Arsenijevic A, Stojanovic B, Strazic Geljic I, Arsenijevic N, Jonjic S, Lukic ML, Milovanovic M. Galectin-3 Deficiency Facilitates TNF-α-Dependent Hepatocyte Death and Liver Inflammation in MCMV Infection. Front Microbiol 2019; 10:185. [PMID: 30800112 PMCID: PMC6376859 DOI: 10.3389/fmicb.2019.00185] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/23/2019] [Indexed: 12/12/2022] Open
Abstract
Galectin-3 (Gal-3) has a role in multiple inflammatory pathways. Various, opposite roles of Gal-3 in liver diseases have been described but there are no data about the role of Gal-3 in development of hepatitis induced with cytomegalovirus infection. In this study we aimed to clarify the role of Gal-3 in murine cytomegalovirus (MCMV)-induced hepatitis by using Gal-3-deficient (Gal-3 KO) mice. Here we provide the evidence that Gal-3 has the protective role in MCMV-induced hepatitis. Enhanced hepatitis manifested by more inflammatory and necrotic foci and serum level of ALT, enhanced apoptosis and necroptosis of hepatocytes and enhanced viral replication were detected in MCMV-infected Gal-3 deficient mice. NK cells does not contribute to more severe liver damage in MCMV-infected Gal-3 KO mice. Enhanced expression of TNF-α in the hepatocytes of Gal-3 KO mice after MCMV infection, abrogated hepatocyte death, and attenuated inflammation in the livers of Gal-3 KO mice after TNF-α blockade suggest that TNF-α plays the role in enhanced disease in Gal-3 deficient animals. Treatment with recombinant Gal-3 reduces inflammation and especially necrosis of hepatocytes in the livers of MCMV-infected Gal-3 KO mice. Our data highlight the protective role of Gal-3 in MCMV-induced hepatitis by attenuation of TNF-α-mediated death of hepatocytes.
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Affiliation(s)
- Bojana Stojanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Faculty of Medical Sciences, Institute of Pathophysiology, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Faculty of Medical Sciences, Institute of Histology, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojan Stojanovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ivana Strazic Geljic
- Department for Histology and Embryology, Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Stipan Jonjic
- Department for Histology and Embryology, Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Miodrag L Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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24
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Bussey KA, Murthy S, Reimer E, Chan B, Hatesuer B, Schughart K, Glaunsinger B, Adler H, Brinkmann MM. Endosomal Toll-Like Receptors 7 and 9 Cooperate in Detection of Murine Gammaherpesvirus 68 Infection. J Virol 2019; 93:e01173-18. [PMID: 30429335 PMCID: PMC6340039 DOI: 10.1128/jvi.01173-18] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/02/2018] [Indexed: 12/13/2022] Open
Abstract
Murine gammaherpesvirus 68 (MHV68) is a small-animal model suitable for study of the human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal Toll-like receptor (TLR) escort protein UNC93B, endosomal TLR7, -9, and -13, and cell surface TLR2 in MHV68 detection. We found that the alpha interferon (IFN-α) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/- cells compared to levels in wild type (WT) cells but not completely lost. Tlr7-/- pDC responded similarly to WT. However, we found that in Unc93b-/- pDC, as well as in Tlr7-/-Tlr9-/- double-knockout pDC, the IFN-α response to MHV68 was completely abolished. Thus, the only pattern recognition receptors contributing to the IFN-α response to MHV68 in pDC are TLR7 and TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and spleen of Tlr7-/-Tlr9-/- mice. The absence of TLR2 or TLR13 did not affect lytic viral titers. We then compared reactivation of MHV68 from latently infected WT, Unc93b-/-, Tlr7-/-Tlr9-/-, Tlr7-/-, and Tlr9-/- splenocytes. We observed enhanced reactivation and latent viral loads, particularly from Tlr7-/-Tlr9-/- splenocytes compared to levels in the WT. Our data show that UNC93B-dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68 infection.IMPORTANCE The two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), can cause aggressive forms of cancer. These herpesviruses are strictly host specific, and therefore the homolog murine gammaherpesvirus 68 (MHV68) is a widely used model to obtain in vivo insights into the interaction between these two gammaherpesviruses and their host. Like EBV and KSHV, MHV68 establishes lifelong latency in B cells. The innate immune system serves as one of the first lines of host defense, with pattern recognition receptors such as the Toll-like receptors playing a crucial role in mounting a potent antiviral immune response to various pathogens. Here, we shed light on a yet unanticipated role of Toll-like receptor 7 in the recognition of MHV68 in a subset of immune cells called plasmacytoid dendritic cells, as well as on the control of this virus in its host.
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Affiliation(s)
- Kendra A Bussey
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Sripriya Murthy
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Elisa Reimer
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Baca Chan
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Bastian Hatesuer
- Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Klaus Schughart
- Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
- University of Veterinary Medicine Hannover, Hannover, Germany
- Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Britt Glaunsinger
- Department of Plant and Microbial Biology, University of California Berkeley, Howard Hughes Medical Institute, Berkeley, California, USA
| | - Heiko Adler
- Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München-German Research Center for Environmental Health, German Center of Lung Research, Munich, Germany
| | - Melanie M Brinkmann
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
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25
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Clement M, Humphreys IR. Cytokine-Mediated Induction and Regulation of Tissue Damage During Cytomegalovirus Infection. Front Immunol 2019; 10:78. [PMID: 30761144 PMCID: PMC6362858 DOI: 10.3389/fimmu.2019.00078] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 01/11/2019] [Indexed: 12/25/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a β-herpesvirus with high sero-prevalence within the human population. Primary HCMV infection and life-long carriage are typically asymptomatic. However, HCMV is implicated in exacerbation of chronic conditions and associated damage in individuals with intact immune systems. Furthermore, HCMV is a significant cause of morbidity and mortality in the immunologically immature and immune-compromised where disease is associated with tissue damage. Infection-induced inflammation, including robust cytokine responses, is a key component of pathologies associated with many viruses. Despite encoding a large number of immune-evasion genes, HCMV also triggers the induction of inflammatory cytokine responses during infection. Thus, understanding how cytokines contribute to CMV-induced pathologies and the mechanisms through which they are regulated may inform clinical management of disease. Herein, we discuss our current understanding based on clinical observation and in vivo modeling of disease of the role that cytokines play in CMV pathogenesis. Specifically, in the context of the different tissues and organs in which CMV replicates, we give a broad overview of the beneficial and adverse effects that cytokines have during infection and describe how cytokine-mediated tissue damage is regulated. We discuss the implications of findings derived from mice and humans for therapeutic intervention strategies and our understanding of how host genetics may influence the outcome of CMV infections.
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Affiliation(s)
- Mathew Clement
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff, United Kingdom
| | - Ian R Humphreys
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff, United Kingdom
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26
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Tomasello E, Naciri K, Chelbi R, Bessou G, Fries A, Gressier E, Abbas A, Pollet E, Pierre P, Lawrence T, Vu Manh TP, Dalod M. Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection. EMBO J 2018; 37:embj.201798836. [PMID: 30131424 PMCID: PMC6166132 DOI: 10.15252/embj.201798836] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 07/23/2018] [Accepted: 07/25/2018] [Indexed: 12/13/2022] Open
Abstract
Plasmacytoid dendritic cells (pDC) are the major source of type I interferons (IFN-I) during viral infections, in response to triggering of endosomal Toll-like receptors (TLRs) 7 or 9 by viral single-stranded RNA or unmethylated CpG DNA, respectively. Synthetic ligands have been used to disentangle the underlying signaling pathways. The adaptor protein AP3 is necessary to transport molecular complexes of TLRs, synthetic CpG DNA, and MyD88 into endosomal compartments allowing interferon regulatory factor 7 (IRF7) recruitment whose phosphorylation then initiates IFN-I production. High basal expression of IRF7 by pDC and its further enhancement by positive IFN-I feedback signaling appear to be necessary for robust cytokine production. In contrast, we show here that in vivo during mouse cytomegalovirus (MCMV) infection pDC produce high amounts of IFN-I downstream of the TLR9-to-MyD88-to-IRF7 signaling pathway without requiring IFN-I positive feedback, high IRF7 expression, or AP3-driven endosomal routing of TLRs. Hence, the current model of the molecular requirements for professional IFN-I production by pDC, established by using synthetic TLR ligands, does not strictly apply to a physiological viral infection.
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Affiliation(s)
- Elena Tomasello
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Karima Naciri
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Rabie Chelbi
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Gilles Bessou
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Anissa Fries
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Elise Gressier
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Abdenour Abbas
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Emeline Pollet
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Philippe Pierre
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Toby Lawrence
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Thien-Phong Vu Manh
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Marc Dalod
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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27
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Abstract
Developing new vaccines against emerging pathogens or pathogens where variability of antigenic sites presents a challenge, the inclusion of stimulators of the innate immune system is critical to mature the immune response in a way that allows high avidity recognition while preserving the ability to react to drifted serovars. The innate immune system is an ancient mechanism for recognition of nonself and the first line of defense against pathogen insult. By triggering innate receptors, adjuvants can boost responses to vaccines and enhance the quality and magnitude of the resulting immune response. This chapter: (1) describes the innate immune system, (2) provides examples of how adjuvants are formulated to optimize their effectiveness, and (3) presents examples of how adjuvants can improve outcomes of immunization.
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Affiliation(s)
- Darrick Carter
- PAI Life Sciences Inc., 1616 Eastlake Ave E, Suite 550, Seattle, WA, 98102, USA.
- Adjuvant Technologies, IDRI, 1616 Eastlake Avenue E., Suite 400, Seattle, WA, 98102, USA.
- Global Health, University of Washington, 1616 Eastlake Ave E, Suite 400, Seattle, WA, 98102, USA.
| | - Malcolm S Duthie
- Adjuvant Technologies, IDRI, 1616 Eastlake Avenue E., Suite 400, Seattle, WA, 98102, USA
- Global Health, University of Washington, 1616 Eastlake Ave E, Suite 400, Seattle, WA, 98102, USA
| | - Steven G Reed
- Adjuvant Technologies, IDRI, 1616 Eastlake Avenue E., Suite 400, Seattle, WA, 98102, USA
- Global Health, University of Washington, 1616 Eastlake Ave E, Suite 400, Seattle, WA, 98102, USA
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28
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Puttur F, Francozo M, Solmaz G, Bueno C, Lindenberg M, Gohmert M, Swallow M, Tufa D, Jacobs R, Lienenklaus S, Kühl AA, Borkner L, Cicin-Sain L, Holzmann B, Wagner H, Berod L, Sparwasser T. Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling. Cell Rep 2017; 17:1113-1127. [PMID: 27760315 DOI: 10.1016/j.celrep.2016.09.055] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 08/09/2016] [Accepted: 09/16/2016] [Indexed: 12/17/2022] Open
Abstract
Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c+ dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity.
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Affiliation(s)
- Franz Puttur
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Marcela Francozo
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany; Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil
| | - Gülhas Solmaz
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Carlos Bueno
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany; Laboratorio de Virología, Departamento de Química Biológica, IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EGA, Argentina
| | - Marc Lindenberg
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Melanie Gohmert
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Maxine Swallow
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Dejene Tufa
- Department of Clinical Immunology and Rheumatology, MHH, 30625 Hannover, Germany
| | - Roland Jacobs
- Department of Clinical Immunology and Rheumatology, MHH, 30625 Hannover, Germany
| | - Stefan Lienenklaus
- Institute for Laboratory Animal Science, MHH, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; Institute for Experimental Infection Research, Twincore, MHH and HZI, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany
| | - Anja A Kühl
- Medical Department (Gastroenterology, Infectious Diseases and Rheumatology)/Research Center ImmunoScience, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany
| | - Lisa Borkner
- Department for Vaccinology/Immune Aging and Chronic Infection, HZI, 38124 Braunschweig, Germany
| | - Luka Cicin-Sain
- Department for Vaccinology/Immune Aging and Chronic Infection, HZI, 38124 Braunschweig, Germany
| | - Bernard Holzmann
- Department of Surgery, Technische Universität München, 81675 Munich, Germany
| | - Hermann Wagner
- Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
| | - Luciana Berod
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
| | - Tim Sparwasser
- Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
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Souquette A, Frere J, Smithey M, Sauce D, Thomas PG. A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. GeroScience 2017. [PMID: 28647907 DOI: 10.1007/s11357-017-9982-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447, 2010) and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012). Following primary infection, CMV establishes lifelong latency with periodic reactivation. Immunocompetent hosts experience largely asymptomatic infection, but CMV can cause serious illness in immunocompromised populations, such as transplant patients and the elderly. Control of CMV requires constant immune surveillance, and recent discoveries suggest this demand alters general features of the immune system in infected individuals. Here, we review recent advances in the understanding of the immune response to CMV and the role of CMV in immune aging and fitness, while highlighting the importance of potential confounding factors that influence CMV studies. Understanding how CMV contributes to shaping "baseline" immunity has important implications for a host's ability to mount effective responses to diverse infections and vaccination.
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Affiliation(s)
- Aisha Souquette
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Justin Frere
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), INSERM U1135, Sorbonne Universités, UPMC DHU FAST, Paris, France.,Arizona Center on Aging, Department of Immunobiology, University of Arizona, Tucson, AZ, USA
| | - Megan Smithey
- Arizona Center on Aging, Department of Immunobiology, University of Arizona, Tucson, AZ, USA
| | - Delphine Sauce
- Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), INSERM U1135, Sorbonne Universités, UPMC DHU FAST, Paris, France
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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30
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Studzińska M, Jabłońska A, Wiśniewska-Ligier M, Nowakowska D, Gaj Z, Leśnikowski ZJ, Woźniakowska-Gęsicka T, Wilczyński J, Paradowska E. Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children. PLoS One 2017; 12:e0169420. [PMID: 28046022 PMCID: PMC5207783 DOI: 10.1371/journal.pone.0169420] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023] Open
Abstract
Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.
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Affiliation(s)
- Mirosława Studzińska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Agnieszka Jabłońska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | - Małgorzata Wiśniewska-Ligier
- Department of Pediatrics, Immunology, and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Dorota Nowakowska
- Department of Perinatology and Gynecology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Zuzanna Gaj
- Department of Perinatology and Gynecology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Zbigniew J. Leśnikowski
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
| | | | - Jan Wilczyński
- 2nd Department of Obstetrics and Gynecology, Warsaw Medical University, Warsaw, Poland
| | - Edyta Paradowska
- Laboratory of Molecular Virology and Biological Chemistry, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
- * E-mail:
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31
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Saeed U, Piracha ZZ. Bridging the importance of Toll like receptors in human viral infections. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(16)61089-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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32
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Sharma S, Fitzgerald KA, Cancro MP, Marshak-Rothstein A. Nucleic Acid-Sensing Receptors: Rheostats of Autoimmunity and Autoinflammation. THE JOURNAL OF IMMUNOLOGY 2015; 195:3507-12. [PMID: 26432899 DOI: 10.4049/jimmunol.1500964] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Distinct families of germline-encoded pattern recognition receptors can sense both microbial and endogenous nucleic acids. These DNA and RNA sensors include endosomal TLRs and cytosolic sensors upstream of stimulator of type I IFN genes (STING) and MAVS. The existence of overlapping specificities for both foreign and self nucleic acids suggests that, under optimal conditions, the activity of these receptors is finely tuned to effectively mediate host defense yet constrain pathogenic self-reactivity. This equilibrium becomes disrupted with the loss of either TLR9 or STING. To maintain immune protection, this loss can be counterbalanced by the elevated response of an alternative receptor(s). Unfortunately, this adjustment can lead to an increased risk for the development of systemic autoimmunity, as evidenced by the exacerbated clinical disease manifestations of TLR9-deficient and STING-deficient autoimmune-prone mice. These studies underscore the delicate balance normally maintained by tonic signals that prevent unchecked immune responses to nucleic acids released during infections and cellular duress or death.
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Affiliation(s)
- Shruti Sharma
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
| | - Katharine A Fitzgerald
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
| | - Michael P Cancro
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104
| | - Ann Marshak-Rothstein
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and
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33
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Yin Y, Qin T, Wang X, Lin J, Yu Q, Yang Q. CpG DNA assists the whole inactivated H9N2 influenza virus in crossing the intestinal epithelial barriers via transepithelial uptake of dendritic cell dendrites. Mucosal Immunol 2015; 8:799-814. [PMID: 25492476 DOI: 10.1038/mi.2014.110] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 10/09/2014] [Indexed: 02/04/2023]
Abstract
Intestinal mucosa remains a pivotal barrier for the oral vaccine absorption of H9N2 whole inactivated influenza virus (WIV). However, CpG DNA, as an adjuvant, can effectively improve relevant mucosal and systemic immunity. The downstream mechanism is well confirmed, yet the evidence of CpG DNA assisting H9N2 WIV in transepithelial delivery is lacking. Here, we reported both in vitro and in vivo that CpG DNA combined with H9N2 WIV was capable of recruiting additional dendritic cells (DCs) to the intestinal epithelial cells (ECs) to form transepithelial dendrites (TEDs) for luminal viral uptake. Both CD103(+) and CD103(-) DCs participated in this process. The engagement of the chemokine CCL20 from the apical ECs and the DCs drove DC recruitment and TED formation. Virus-loaded CD103(+) but not CD103(-) DCs also quickly migrated into mesenteric lymph nodes within 2 h. Moreover, the mechanism of CpG DNA was independent of epithelial transcytosis and disruption of the epithelial barriers. Finally, the subsequent phenotypic and functional maturation of DCs was also enhanced. Our findings indicated that CpG DNA improved the delivery of H9N2 WIV via TEDs of intestinal DCs, and this may be an important mechanism for downstream effective antigen-specific immune responses.
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Affiliation(s)
- Y Yin
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
| | - T Qin
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
| | - X Wang
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
| | - J Lin
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
| | - Q Yu
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
| | - Q Yang
- Key Lab of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, Jiangsu, People's Republic of China
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34
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Cocita C, Guiton R, Bessou G, Chasson L, Boyron M, Crozat K, Dalod M. Natural Killer Cell Sensing of Infected Cells Compensates for MyD88 Deficiency but Not IFN-I Activity in Resistance to Mouse Cytomegalovirus. PLoS Pathog 2015; 11:e1004897. [PMID: 25954804 PMCID: PMC4425567 DOI: 10.1371/journal.ppat.1004897] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 04/20/2015] [Indexed: 01/09/2023] Open
Abstract
In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses increases susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 is dispensable for antiviral immunity. Hence, a higher redundancy has been proposed in the mechanisms promoting protective immune responses against systemic infections by herpes viruses during natural infections in humans. It has been assumed, but not proven, that mice fail to mount protective MyD88-independent IFN-I responses. In humans, the mechanism that compensates MyD88 deficiency has not been elucidated. To address these issues, we compared resistance to MCMV infection and immune responses between mouse strains deficient for MyD88, the IFN-I receptor and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 or TLR9 drastically decreased production of IFN-I, but not the protective antiviral responses. Moreover, MyD88, but not IFN-I receptor, deficiency could largely be compensated by Ly49H-mediated antiviral NK cell responses. Thus, contrary to the current dogma but consistent with the situation in humans, we conclude that, in mice, in our experimental settings, MyD88 is redundant for IFN-I responses and overall defense against a systemic herpes virus infection. Moreover, we identified direct NK cell sensing of infected cells as one mechanism able to compensate for MyD88 deficiency in mice. Similar mechanisms likely contribute to protect MyD88- or IRAK4-deficient patients from viral infections. Type I interferons (IFN-I) are innate cytokines crucial for vertebrate antiviral defenses. IFN-I exert antiviral effector functions and orchestrate antiviral immunity. IFN-I are induced early after infection, upon sensing of viral particles or infected cells by immune receptors. Intracellular Toll-like receptors (TLR) are selectively expressed in specialized immune cell types such as plasmacytoid dendritic cells (pDC), enabling them to copiously produce IFN-I upon detection of engulfed viral nucleic acids. pDC or intracellular TLR have been reported to be crucial for resistance to experimental infections with many viruses in mice but dispensable for resistance to natural infections in humans. Our aim was to investigate this puzzling difference. Mice deficient for TLR activity mounted strong IFN-I responses despite producing very low IFN-I levels and controlled the infection by a moderate dose of murine cytomegalovirus much better than mice deficient for IFN-I responses. Deficient TLR responses could be compensated by direct recognition of infected cells by natural killer cells. Hence, we identified experimental conditions in mice mimicking the lack of requirement of TLR functions for antiviral defense observed in humans. We used these experimental models to advance our basic understanding of antiviral immunity in a way that might help improve treatments for patients.
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MESH Headings
- Animals
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Dendritic Cells/virology
- Gene Expression Profiling
- Gene Expression Regulation
- Herpesviridae Infections/blood
- Herpesviridae Infections/immunology
- Herpesviridae Infections/metabolism
- Herpesviridae Infections/virology
- Host-Pathogen Interactions
- Immunity, Innate
- Immunologic Deficiency Syndromes/immunology
- Immunologic Deficiency Syndromes/metabolism
- Immunologic Deficiency Syndromes/virology
- Interferon Type I/blood
- Interferon Type I/metabolism
- Interleukin-12/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/virology
- Mice, Inbred BALB C
- Mice, Knockout
- Mice, Mutant Strains
- Muromegalovirus/immunology
- Muromegalovirus/physiology
- Myeloid Differentiation Factor 88/deficiency
- Myeloid Differentiation Factor 88/genetics
- Myeloid Differentiation Factor 88/metabolism
- NK Cell Lectin-Like Receptor Subfamily A/deficiency
- NK Cell Lectin-Like Receptor Subfamily A/genetics
- NK Cell Lectin-Like Receptor Subfamily A/metabolism
- Primary Immunodeficiency Diseases
- Receptor, Interferon alpha-beta/agonists
- Receptor, Interferon alpha-beta/deficiency
- Receptor, Interferon alpha-beta/genetics
- Receptor, Interferon alpha-beta/metabolism
- Signal Transduction
- Specific Pathogen-Free Organisms
- Spleen/immunology
- Spleen/metabolism
- Spleen/virology
- Toll-Like Receptor 9/deficiency
- Toll-Like Receptor 9/genetics
- Toll-Like Receptor 9/metabolism
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Affiliation(s)
- Clément Cocita
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Rachel Guiton
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Gilles Bessou
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Lionel Chasson
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Marilyn Boyron
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Karine Crozat
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
| | - Marc Dalod
- Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
- Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
- * E-mail:
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35
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Biron CA, Tarrio ML. Immunoregulatory cytokine networks: 60 years of learning from murine cytomegalovirus. Med Microbiol Immunol 2015; 204:345-54. [PMID: 25850988 DOI: 10.1007/s00430-015-0412-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/23/2015] [Indexed: 10/23/2022]
Abstract
Innate immunity defends against infection but also mediates immunoregulatory effects shaping innate and adaptive responses. Studies of murine cytomegalovirus (MCMV) infections have helped elucidate the mechanisms inducing, as well as the elicited soluble and cellular networks contributing to, innate immunity. Specialized receptors are engaged by infection-induced structures to stimulate production of key innate cytokines. These then stimulate cytokine and cellular responses such as activation of natural killer (NK) cells to mediate elevated killing by type 1 interferon (IFN) and/or to produce the pro-inflammatory and antiviral cytokine IFN-γ by interleukin 12 (IL-12). An inter-systemic loop, with IL-6 inducing glucocorticoid release, negatively regulates these early cytokine responses. As infections advance into periods of overlapping innate and adaptive responses, however, the cells are intrinsically conditioned to modify the biological effects of exposure to individual cytokines. Some pathways are turned off to inhibit an existing, whereas others are broadened for acquisition of a new, response function. Remarkably, extended NK cell proliferation during MCMV infection is associated with epigenetic modifications shifting the state of the inhibitory cytokine IL-10 gene from closed to open and results in their becoming equipped to produce this cytokine. When induced, NK cell IL-10 negatively regulates the magnitude of adaptive responses to protect against immune pathology. Thus, innate immunoregulatory cytokine networks are integral to pro-inflammatory and defense functions, but responding cells have the flexibility to undergo cell intrinsic conditioning with changing network characteristics to result in a new negative immunoregulatory function, and consequently, both promote beneficial and limit detrimental immune responses.
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Affiliation(s)
- Christine A Biron
- Department of Molecular Microbiology and Immunology, The Division of Biology and Medicine and The Warren Alpert Medical School, Brown University, 171 Meeting Street, Providence, RI, 02912, USA,
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36
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Brinkmann MM, Dağ F, Hengel H, Messerle M, Kalinke U, Čičin-Šain L. Cytomegalovirus immune evasion of myeloid lineage cells. Med Microbiol Immunol 2015; 204:367-82. [PMID: 25776081 DOI: 10.1007/s00430-015-0403-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 02/28/2015] [Indexed: 12/23/2022]
Abstract
Cytomegalovirus (CMV) evades the immune system in many different ways, allowing the virus to grow and its progeny to spread in the face of an adverse environment. Mounting evidence about the antiviral role of myeloid immune cells has prompted the research of CMV immune evasion mechanisms targeting these cells. Several cells of the myeloid lineage, such as monocytes, dendritic cells and macrophages, play a role in viral control, but are also permissive for CMV and are naturally infected by it. Therefore, CMV evasion of myeloid cells involves mechanisms that qualitatively differ from the evasion of non-CMV-permissive immune cells of the lymphoid lineage. The evasion of myeloid cells includes effects in cis, where the virus modulates the immune signaling pathways within the infected myeloid cell, and those in trans, where the virus affects somatic cells targeted by cytokines released from myeloid cells. This review presents an overview of CMV strategies to modulate and evade the antiviral activity of myeloid cells in cis and in trans.
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Affiliation(s)
- Melanie M Brinkmann
- Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124, Brunswick, Germany
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37
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Mori DN, Kreisel D, Fullerton JN, Gilroy DW, Goldstein DR. Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 2015; 258:132-44. [PMID: 24517430 DOI: 10.1111/imr.12146] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation.
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Affiliation(s)
- Daniel N Mori
- Departments of Internal Medicine and Immunobiology, Yale School of Medicine, New Haven, CT, USA
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38
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Qi Y, Chen S, Zhao Q, Wang M, Jia R, Zhu D, Liu M, Liu F, Chen X, Cheng A. Molecular cloning, tissue distribution, and immune function of goose TLR7. Immunol Lett 2014; 163:135-42. [PMID: 25497239 DOI: 10.1016/j.imlet.2014.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 11/17/2014] [Accepted: 11/22/2014] [Indexed: 01/27/2023]
Abstract
TLR7 is a transmembrane endosomal protein that plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. Here, we cloned the full-length cDNA of goose TLR7 and carried out a molecular characterization of goose TLR7. The goose TLR7 gene is 3900 bp and encodes a 1045 amino acid protein with high homology to poultry (93% to duck and 83% to chicken). Similar conclusions were made by phylogenetic analysis. The predicted protein secondary structure of goose TLR7 contained a conserved Toll/interleukin-1 receptor domain and characteristic leucine-rich repeat regions, which has also been reported for duck TLR7. Additionally, the tissue distribution of goose TLR7 suggests that immune-associated tissues, especially the cecal tonsil and bursa of Fabricius, have high goose TLR7 expression levels. Goose TLR7 is abundantly expressed in lung tissues, which is distinct from its expression in chickens. Similar to duck TLR7, goose spleen mononuclear cells (MNCs) exposed to the mammalian TLR7 agonists R848 and Imiquimod showed significant induction of the production of proinflammatory cytokines and IFN-α. New type gosling viral enteritis virus (NGVEV) infection resulted in high mRNA expression levels of goose TLR7 in the spleen. By contrast, no direct interaction between NGVEV and goose TLR7 was detected after infecting goose spleen MNCs with NGVEV in vitro. However, triggering of goose TLR7 resulted in the rapid up-regulation of proinflammatory cytokines and anti-viral molecules, suggesting that goose TLR7 plays an important role in anti-viral defense.
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Affiliation(s)
- Yulin Qi
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China.
| | - Qiurong Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Dekang Zhu
- Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Fei Liu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Xiaoyue Chen
- Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Avian Disease Research Center, College of Veterinary Medicine of Sichuan Agricultural University, Ya'an, Sichuan 625014, PR China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China.
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Del Prete A, Luganini A, Scutera S, Rossi S, Anselmo A, Greco D, Landolfo S, Badolato R, Gribaudo G, Sozzani S, Musso T. Interferon-α production by plasmacytoid dendritic cells is dispensable for an effective anti-cytomegalovirus response in adaptor protein-3-deficient mice. J Interferon Cytokine Res 2014; 35:232-8. [PMID: 25333950 DOI: 10.1089/jir.2013.0110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Adaptor protein-3 (AP-3) is a heterotetrameric complex, which regulates vesicular trafficking. Mutations of the β3A subunit cause the Hermansky-Pudlak syndrome type 2 (HPS-2), a rare genetic disease characterized by albinism, platelet defects, and recurrent infections. Likewise, pearl mice, which lack functional AP-3, show several HPS-2 defects. The AP-3 absence results in defective toll-like receptor trafficking and signaling in dendritic cells (DC), but its effect on the efficiency of the in vivo antiviral response is unclear. We evaluated the impact of AP-3 deficiency on the distribution of DC subsets, interferon (IFN) production, and the susceptibility to murine cytomegalovirus (MCMV) infection. Pearl mice showed a distribution and frequency of conventional (cDC) and plasmacytoid DC (pDC) similar to that of wild-type mice both before and after MCMV infection. Moreover, pearl mice controlled MCMV infection even at high virus doses and showed a normal production of IFN-α. Since pDC, but not cDC, from pearl mice showed an impaired IFN-α and tumor necrosis factor-α production in response to prototypic DNA (MCMV and Herpes Simplex virus) or RNA (Vesicular Stomatitis virus) viruses in vitro, it is likely that MCMV infection can be controlled in vivo independently of an efficient production of IFN-α by pDC, and that the AP-3 complex has a minimal impact on protective antiviral responses.
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Affiliation(s)
- Annalisa Del Prete
- 1 Department of Molecular and Translational Medicine, University of Brescia , Brescia, Italy
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Uchiyama R, Chassaing B, Zhang B, Gewirtz AT. MyD88-mediated TLR signaling protects against acute rotavirus infection while inflammasome cytokines direct Ab response. Innate Immun 2014; 21:416-28. [PMID: 25213347 DOI: 10.1177/1753425914547435] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 07/24/2014] [Indexed: 11/16/2022] Open
Abstract
Rotavirus (RV) infects small intestinal epithelial cells, inducing severe diarrhea in children, resulting in over 500,000 deaths annually. Relatively little is known about how innate immunity contains acute infection and drives adaptive immune responses that afford complete clearance of RV and protection against future infection. Hence, we examined the consequence of the absence of MyD88, known to be central to innate immunity, in a mouse model of RV infection. The absence of MyD88, but not combined blockade of IL-1β and IL-18 signaling, resulted in greater infectivity, as reflected by levels of RV in feces, intestinal lysates and viremia. Such increased RV levels correlated with an increase in incidence and duration of diarrhea. Loss of MyD88 also impaired humoral immunity to RV. Specifically, MyD88 knockout generated less RV-specific IgA and exhibited profoundly reduced RV-specific IgG2c/IgG1 ratios suggesting that MyD88 signaling drives RV-induced Th1 responses. A study of MyD88 bone marrow chimeras indicated that MyD88-dependent control of acute RV infection was mediated by both hemopoietic and non-hemopoietic cells, while generation of RV-specific humoral immunity was driven by MyD88 signaling in hemopoietic cells, which reflected the loss of IL-1β and IL-18 expression by these cells. Thus, TLR signaling and inflammasome cytokines drive innate and adaptive immunity to RV.
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Affiliation(s)
- Robin Uchiyama
- Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, GA, USA
| | - Benoit Chassaing
- Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Benyue Zhang
- Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Andrew T Gewirtz
- Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, GA, USA
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Patel MC, Shirey KA, Pletneva LM, Boukhvalova MS, Garzino-Demo A, Vogel SN, Blanco JC. Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol 2014; 9:811-829. [PMID: 25620999 DOI: 10.2217/fvl.14.70] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.
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Affiliation(s)
- Mira C Patel
- Department of Microbiology & Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
| | - Kari Ann Shirey
- Department of Microbiology & Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
| | | | | | - Alfredo Garzino-Demo
- Department of Microbiology & Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA ; Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
| | - Stefanie N Vogel
- Department of Microbiology & Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
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Alexandre YO, Cocita CD, Ghilas S, Dalod M. Deciphering the role of DC subsets in MCMV infection to better understand immune protection against viral infections. Front Microbiol 2014; 5:378. [PMID: 25120535 PMCID: PMC4114203 DOI: 10.3389/fmicb.2014.00378] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/04/2014] [Indexed: 12/22/2022] Open
Abstract
Infection of mice with murine cytomegalovirus (MCMV) recapitulates many physiopathological characteristics of human CMV infection and enables studying the interactions between a virus and its natural host. Dendritic cells (DC) are mononuclear phagocytes linking innate and adaptive immunity which are both necessary for MCMV control. DC are critical for the induction of cellular immunity because they are uniquely efficient for the activation of naïve T cells during their first encounter with a pathogen. DC are equipped with a variety of innate immune recognition receptors (I2R2) allowing them to detect pathogens or infections and to engulf molecules, microorganisms or cellular debris. The combinatorial engagement of I2R2 during infections controls DC maturation and shapes their response in terms of cytokine production, activation of natural killer (NK) cells and functional polarization of T cells. Several DC subsets exist which express different arrays of I2R2 and are specialized in distinct functions. The study of MCMV infection helped deciphering the physiological roles of DC subsets and their molecular regulation. It allowed the identification and first in vivo studies of mouse plasmacytoid DC which produce high level of interferons-α/β early after infection. Despite its ability to infect DC and dampen their functions, MCMV induces very robust, efficient and long-lasting CD8 T cell responses. Their priming may rely on the unique ability of uninfected XCR1+ DC to cross-present engulfed viral antigens and thus to counter MCMV interference with antigen presentation. A balance appears to have been reached during co-evolution, allowing controlled replication of the virus for horizontal spread without pathological consequences for the immunocompetent host. We will discuss the role of the interplay between the virus and DC in setting this balance, and how advancing this knowledge further could help develop better vaccines against other intracellular infectious agents.
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Affiliation(s)
- Yannick O Alexandre
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2 Marseille, France ; Institut National de la Santé et de la Recherche Médicale, U1104 Marseille, France ; Centre National de la Recherche Scientifique, UMR7280 Marseille, France
| | - Clément D Cocita
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2 Marseille, France ; Institut National de la Santé et de la Recherche Médicale, U1104 Marseille, France ; Centre National de la Recherche Scientifique, UMR7280 Marseille, France
| | - Sonia Ghilas
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2 Marseille, France ; Institut National de la Santé et de la Recherche Médicale, U1104 Marseille, France ; Centre National de la Recherche Scientifique, UMR7280 Marseille, France
| | - Marc Dalod
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2 Marseille, France ; Institut National de la Santé et de la Recherche Médicale, U1104 Marseille, France ; Centre National de la Recherche Scientifique, UMR7280 Marseille, France
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Rahim MMA, Tu MM, Mahmoud AB, Wight A, Abou-Samra E, Lima PDA, Makrigiannis AP. Ly49 receptors: innate and adaptive immune paradigms. Front Immunol 2014; 5:145. [PMID: 24765094 PMCID: PMC3980100 DOI: 10.3389/fimmu.2014.00145] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 03/20/2014] [Indexed: 11/13/2022] Open
Abstract
The Ly49 receptors are type II C-type lectin-like membrane glycoproteins encoded by a family of highly polymorphic and polygenic genes within the mouse natural killer (NK) gene complex. This gene family is designated Klra, and includes genes that encode both inhibitory and activating Ly49 receptors in mice. Ly49 receptors recognize class I major histocompatibility complex-I (MHC-I) and MHC-I-like proteins on normal as well as altered cells. Their functional homologs in humans are the killer cell immunoglobulin-like receptors, which recognize HLA class I molecules as ligands. Classically, Ly49 receptors are described as being expressed on both the developing and mature NK cells. The inhibitory Ly49 receptors are involved in NK cell education, a process in which NK cells acquire function and tolerance toward cells that express “self-MHC-I.” On the other hand, the activating Ly49 receptors recognize altered cells expressing activating ligands. New evidence shows a broader Ly49 expression pattern on both innate and adaptive immune cells. Ly49 receptors have been described on multiple NK cell subsets, such as uterine NK and memory NK cells, as well as NKT cells, dendritic cells, plasmacytoid dendritic cells, macrophages, neutrophils, and cells of the adaptive immune system, such as activated T cells and regulatory CD8+ T cells. In this review, we discuss the expression pattern and proposed functions of Ly49 receptors on various immune cells and their contribution to immunity.
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Affiliation(s)
- Mir Munir A Rahim
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada
| | - Megan M Tu
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada
| | - Ahmad Bakur Mahmoud
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada ; College of Applied Medical Sciences, Taibah University , Madinah Munawwarah , Kingdom of Saudi Arabia
| | - Andrew Wight
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada
| | - Elias Abou-Samra
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada
| | - Patricia D A Lima
- Biomedical and Molecular Sciences, Queen's University , Kingston, ON , Canada
| | - Andrew P Makrigiannis
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, ON , Canada
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Della Chiesa M, Marcenaro E, Sivori S, Carlomagno S, Pesce S, Moretta A. Human NK cell response to pathogens. Semin Immunol 2014; 26:152-60. [PMID: 24582551 DOI: 10.1016/j.smim.2014.02.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 02/04/2014] [Indexed: 12/23/2022]
Abstract
NK cells represent important effectors of the innate immunity in the protection of an individual from microbes. During an NK-mediated anti-microbial response, the final fate (survival or death) of a potential infected target cell depends primarily on the type and the number of receptor/ligand interactions occurring at the effector/target immune synapse. The identification of an array of receptors involved in NK cell triggering has been crucial for a better understanding of the NK cell biology. In this context, NCR play a predominant role in NK cell activation during the process of natural cytotoxicity. Regarding the NK-mediated pathogen recognition and NK cell activation, an emerging concept is represented by the involvement of TLRs and activating KIRs. NK cells express certain TLRs in common with other innate cell types. This would mean that specific TLR ligands are able to promote the simultaneous and synergistic stimulation of these innate cells, providing a coordinated mechanism for regulating the initiation and amplification of immune responses. Evidences have been accumulated indicating that viral infections may have a significant impact on NK cell maturation, promoting the expansion of phenotypically and functionally aberrant NK cell subpopulations. For example, during chronic HIV-infection, an abnormal expansion of a dysfunctional CD56neg NK cell subset has been detected that may explain, at least in part, the defective NK cell-mediated antiviral activity. An analogous imbalance of NK cell subsets has been detected in patients receiving HSCT to cure high risk leukemias and experiencing HCMV infection/reactivation. Remarkably, NK cells developing after CMV reactivation may contain "memory-like" or "long-lived" NK cells that could exert a potent anti-leukemia effect.
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Affiliation(s)
- Mariella Della Chiesa
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Emanuela Marcenaro
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Simona Sivori
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Simona Carlomagno
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Silvia Pesce
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Alessandro Moretta
- DI.ME.S. Dipartimento di Medicina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy.
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Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. PLoS Pathog 2014; 10:e1003960. [PMID: 24586164 PMCID: PMC3930590 DOI: 10.1371/journal.ppat.1003960] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 01/14/2014] [Indexed: 01/04/2023] Open
Abstract
Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts. Epstein-Barr virus (EBV) is a human herpesvirus that persistently infects >90% of adults worldwide. One factor underlying the ability of EBV to establish such widespread and lifelong infections is its capacity to escape elimination by the human immune system. Among the first lines of defense against viral infection is the human Toll-like receptor (TLR) system. These receptors can detect the presence of viruses and initiate an intracellular protein signaling cascade that leads to the expression of immune response genes. The activation status of many proteins in this signaling cascade is regulated by the addition of ubiquitin tags. EBV has previously been reported to encode enzymes, called deubiquitinases (DUBs), which are capable of removing such ubiquitin tags from substrate proteins. In our study, we found that one of these enzymes, BPLF1, functions as an active DUB during EBV production in infected cells before being packaged into newly produced viral particles. Furthermore, our study provides insight into the way in which EBV can subvert the human immune response, as we show that BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes.
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46
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Toll-like receptor activation and expression in bovine alpha-herpesvirus infections. Res Vet Sci 2014; 96:196-203. [DOI: 10.1016/j.rvsc.2013.11.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 10/07/2013] [Accepted: 11/30/2013] [Indexed: 01/19/2023]
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MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. J Virol 2014; 88:3557-67. [PMID: 24403581 DOI: 10.1128/jvi.02776-13] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCE Vaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.
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Huang YW, Hsu CK, Lin SC, Wei SC, Hu JT, Chang HY, Liang CW, Chen DS, Chen PJ, Hsu PN, Yang SS, Kao JH. Reduced Toll-like receptor-9 expression on peripheral CD14+ monocytes of chronic hepatitis B patients and its restoration by effective therapy. Antivir Ther 2014; 19:637-43. [DOI: 10.3851/imp2762] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2013] [Indexed: 10/25/2022]
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Wikstrom ME, Khong A, Fleming P, Kuns R, Hertzog PJ, Frazer IH, Andoniou CE, Hill GR, Degli-Esposti MA. The early monocytic response to cytomegalovirus infection is MyD88 dependent but occurs independently of common inflammatory cytokine signals. Eur J Immunol 2013; 44:409-19. [PMID: 24166710 DOI: 10.1002/eji.201243109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 09/26/2013] [Accepted: 10/18/2013] [Indexed: 11/09/2022]
Abstract
Cytomegalovirus latently infects myeloid cells; however, the acute effects of the virus on this cell subset are poorly characterised. We demonstrate that systemic cytomegalovirus infection induced rapid activation of monocytes in the bone marrow, characterised by upregulation of CD69, CD11c, Ly6C and M-CSF receptor. Activated bone marrow monocytes were more sensitive to M-CSF and less sensitive to granulocyte-monocyte colony stimulating factor in vitro, resulting in the generation of more macrophages and fewer dendritic cells, respectively. Monocyte activation was also observed in the periphery and resulted in significant accumulation of monocytes in the spleen. MyD88 expression was required within the haematopoietic compartment to initiate monocyte activation and recruitment. However, monocytes lacking MyD88 were activated and recruited in the presence of MyD88-sufficient cells in mixed bone marrow chimeras, indicating that once initiated, the process was MyD88 independent. Interestingly, we found that monocyte activation occurred in the absence of the common inflammatory cytokines, namely type I interferons (IFNs), IL-6, TNF-α and IL-1 as well as the NLRP3 inflammasome adaptor protein, ASC. We also excluded a role for the chemokine-like protein MCK-2 (m131/129) expressed by murine CMV. Taken together, these results challenge the notion that a single inflammatory cytokine mediates activation and recruitment of monocytes in response to infection.
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Affiliation(s)
- Matthew E Wikstrom
- Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
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Abstract
During mouse cytomegalovirus (MCMV) infection, the first wave of type I interferon (IFN-I) production peaks at ≈ 8 h. This IFN-I emanates from splenic stromal cells located in the marginal zone (MZ) and requires B cells that express lymphotoxin. The amount of IFN-I produced at these initial times is at least equivalent in magnitude to that produced later by dendritic cells (≈ 36 to 48 h), but the relative roles of these two IFN-I sources in regulating MCMV defense remain unclear. Here we show that IFN-I produced by MZ stromal cells dramatically restricts the first measurable burst of viral production, which occurs at ≈ 32 h. This primary innate control by IFN-I is partially mediated through the activation of natural killer (NK) cells, which produce gamma interferon in an IFN-I-dependent fashion, and is independent of Ly49H. Strikingly, MCMV production in the spleens of immunocompetent mice never increases at times after 32 h. These results highlight the critical importance of lymphoid-tissue stromal cells in orchestrating the earliest phase of innate defense to MCMV infection, capping replication levels, and blocking spread until infection is ultimately controlled.
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