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Liao TL, Chen YM, Tang KT, Yang YY, Chen DY, Chan TH, Tsai HJ, Hsieh SL. CLEC18A Impairs Phagocytosis by Reducing FcγRIIA Expression and Arresting Autophagosome-Lysosome Fusion. Microbiol Spectr 2023; 11:e0290322. [PMID: 37154715 PMCID: PMC10269929 DOI: 10.1128/spectrum.02903-22] [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: 07/27/2022] [Accepted: 03/28/2023] [Indexed: 05/10/2023] Open
Abstract
Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC (P < 0.005). We demonstrated that CLEC18A could inhibit FcγRIIA expression in a dose-dependent manner through the production of NOX-2-dependent reactive oxygen species to impair the uptake of ICs. Additionally, CLEC18A suppresses the Rab7 expression that is induced by starvation. Overexpressed CLEC18A does not affect autophagosome formation but does reduce the recruitment of Rab7 to autophagosomes, thereby retarding the maturation of autophagosomes and affecting autophagosome-lysosome fusion. We offer a novel molecular machinery with which to understand the association of HCV infection with autoimmunity and propose that CLEC18A may act as a candidate biomarker for HCV-associated MC. IMPORTANCE During infection, the host immune system produces cellular factors to protect against pathogen invasion. However, when the immune response overreacts and there is dysregulated cytokine homeostasis, autoimmunity occurs following an infection. We identified a cellular factor that is involved in HCV-related extrahepatic manifestation, namely, CLEC18A, which is expressed abundantly in hepatocytes and phagocytes. It inhibits HCV replication in hepatocytes by interacting with Rab5/7 and enhancing type I/III IFN expression. However, overexpressed CLEC18A inhibited FcγRIIA expression in phagocytes to impair phagocytosis. Furthermore, the interaction between CLEC18A and Rab5/7 may reduce the recruitment of Rab7 to autophagosomes and thereby retard autophagosome maturation and cause immune complex accumulation. A decreasing trend in CLEC18A levels that was accompanied by reduced HCV RNA titers and diminished cryoglobulin was observed in the sera of HCV-MC patients after direct-acting antiviral therapy. CLEC18A may be used for the evaluation of anti-HCV therapeutic drug effects and could be a potential predisposing factor for the development of MC syndrome.
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Affiliation(s)
- Tsai-Ling Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kuo-Tung Tang
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ying-Ying Yang
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Der-Yuan Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Tsung-Hsien Chan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hui-Ju Tsai
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Shie-Liang Hsieh
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
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Kropp DR, Hodes GE. Sex differences in depression: An immunological perspective. Brain Res Bull 2023; 196:34-45. [PMID: 36863664 DOI: 10.1016/j.brainresbull.2023.02.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/05/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023]
Abstract
Depression is a heterogenous disorder with symptoms that present differently across individuals. In a subset of people depression is associated with alterations of the immune system that may contribute to disorder onset and symptomology. Women are twice as likely to develop depression and on average have a more sensitive adaptive and innate immune system when compared to men. Sex differences in pattern recognition receptors (PRRs), release of damage-associated molecular patterns (DAMPs), cell populations, and circulating cytokines play a critical role in inflammation onset. Sex differences in innate and adaptive immunity change the response of and repair to damage caused by dangerous pathogens or molecules in the body. This article reviews the evidence for sex specific immune responses that contribute to the sex differences in symptoms of depression that may account for the higher rate of depression in women.
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Affiliation(s)
- Dawson R Kropp
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Georgia E Hodes
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
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Tian X, Nanding K, Dai X, Wang Q, Wang J, Morigen, Fan L. Pattern recognition receptor mediated innate immune response requires a Rif-dependent pathway. J Autoimmun 2023; 134:102975. [PMID: 36527784 DOI: 10.1016/j.jaut.2022.102975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 12/02/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
Small GTPases play critical roles in cell morphology, movement, and adhesion by dynamic regulation of actin cytoskeleton. The small Rho GTPase Rif/RhoF (Rho in filopodia) regulates the formation of filopodia and stress fibers in cells. Rif is highly expressed in a number of cell types in the immune system; however, it's role in immune system function is unclear. In this research, we found that Rif expression is necessary for NF-κB activation in primary immune cells, and mature dendritic cell (mature DCs) induced from Bone Marrow-Derived Dendritic Cells (BMDCs) isolated from Rif knock out (Rif KO) mice displayed impaired degradation of I-κBα, as well as reduced TNF-α secretion and p38 MAPK phosphorylation under LPS stimulation. Interestingly, we revealed that TLR agonists, such as LPS and poly (I:C), as well as bacterial virulence factor SopE could induce a transient increase in Rif activation in monocytes THP-1 cells. Furthermore, Rif was found to be an integral part of the TLR4, TLR3 and nodosome signaling complex. We further identified Src tyrosine kinases as upstream activator of Rif in both bacterial and viral induced immune responses. Moreover, activated Rif induces activation of transcription factors, such as NF-κB, AP-1 and IRF-3, and mediates inflammation through secretion of IL-6, IL-8 or TNFα. Rif activation by PRRs contributes in a variety of ways to protective host responses against invading microbes. Taken together, this study reveals that Rif is indispensable for both extracellular and intracellular pattern-recognition receptor-mediated innate immune responses. Rif possess broad anti-pathogenic effect and understanding of the molecular mechanisms by which this small Rho GTPase interferes with innate immune system will be beneficial to develop therapies against infectious agents.
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Affiliation(s)
- Xiaoxia Tian
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China; The Laboratory for Tumor Molecular Diagnosis, Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Kathleen Nanding
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Xueyao Dai
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Qian Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Junyu Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China
| | - Morigen
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China.
| | - Lifei Fan
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, 010020, PR China.
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Tiruvayipati S, Hameed DS, Ahmed N. Play the plug: How bacteria modify recognition by host receptors? Front Microbiol 2022; 13:960326. [PMID: 36312954 PMCID: PMC9615552 DOI: 10.3389/fmicb.2022.960326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
The diverse microbial community that colonizes the gastrointestinal tract has remarkable effects on the host immune system and physiology resulting in homeostasis or disease. In both scenarios, the gut microbiota interacts with their host through ligand-receptor binding whereby the downstream signaling processes determine the outcome of the interaction as disease or the counteractive immune responses of the host. Despite several studies on microbe-host interactions and the mechanisms by which this intricate process happens, a comprehensive and updated inventory of known ligand-receptor interactions and their roles in disease is paramount. The ligands which originate as a result of microbial responses to the host environment contribute to either symbiotic or parasitic relationships. On the other hand, the host receptors counteract the ligand actions by mounting a neutral or an innate response. The varying degrees of polymorphic changes in the host receptors contribute to specificity of interaction with the microbial ligands. Additionally, pathogenic microbes manipulate host receptors with endogenous enzymes belonging to the effector protein family. This review focuses on the diversity and similarity in the gut microbiome-host interactions both in health and disease conditions. It thus establishes an overview that can help identify potential therapeutic targets in response to critically soaring antimicrobial resistance as juxtaposed to tardy antibiotic development research.
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Affiliation(s)
- Suma Tiruvayipati
- Infectious Diseases Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Dharjath S. Hameed
- Department of Chemical Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Niyaz Ahmed
- Pathogen Biology Laboratory, Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, India
- *Correspondence: Niyaz Ahmed, ,
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Khalil FO, Alsebaey A, Kasemy ZA, Abdelmageed SM, Bedair HM, Abdelsattar S. IL28B, TLR7 SNPs, and cytomegalovirus infection are risk factors for advanced liver disease in chronic hepatitis C patients. Expert Rev Anti Infect Ther 2022. [DOI: https://doi.org/10.1080/14787210.2021.1935239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Fatma Omar Khalil
- Department of Microbiology and Immunology, National Liver Institute, Egypt
| | - Ayman Alsebaey
- Department of Hepatology and Gastroenterology, National Liver Institute, Egypt
| | | | | | - Hanan Mosaad Bedair
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shebeen El-Koom, Egypt
| | - Shimaa Abdelsattar
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Egypt
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Khalil FO, Alsebaey A, Kasemy ZA, Abdelmageed SM, Bedair HM, Abdelsattar S. IL28B, TLR7 SNPs, and cytomegalovirus infection are risk factors for advanced liver disease in chronic hepatitis C patients. Expert Rev Anti Infect Ther 2022; 20:121-129. [PMID: 34047252 DOI: 10.1080/14787210.2021.1935239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic hepatitis C (CHC) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). This study aimed to study the association of IL28B, toll-like receptor (TLR) 7, cytomegalovirus and advanced liver disease. METHODS Four groups were included; control (n = 125, 25.9%), CHC (n = 114, 23.6%), liver cirrhosis (n = 120, 24.8%), and HCC (n = 124, 25.7%). RESULTS In CHC group, patients were mainly F1 (60%) followed by F2. IL28B genotype CC percentage was higher in control group than the CHC and cirrhosis groups. CT and TT genotypes were higher in the CHC and cirrhosis groups than control group. The C allele was higher in the control group than the CHC, cirrhosis and HCC groups and the opposite with the T allele. Control and CHC had same TLR7 alleles. Cirrhosis patients and HCC had lower TLR 7 A allele and higher G allele than the control group. Both cirrhosis and HCC groups had statistically significant higher percentage of the AG and GG genotypes than the control group. Patients with HCC had higher cytomegalovirus infection percentage than cirrhosis and CHC group (38.7% vs 20% vs 16.7%), respectively. CONCLUSION IL28B, TLR7 SNPs and cytomegalovirus infection are risk factors for advanced liver disease in hepatitis C patients.
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Affiliation(s)
- Fatma Omar Khalil
- Department of Microbiology and Immunology, National Liver Institute, Egypt
| | - Ayman Alsebaey
- Department of Hepatology and Gastroenterology, National Liver Institute, Egypt
| | | | | | - Hanan Mosaad Bedair
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shebeen El-Koom, Egypt
| | - Shimaa Abdelsattar
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Egypt
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Alseoudy MM, Elgamal M, Abdelghany DA, Borg AM, El-Mesery A, Elzeiny D, Hammad MO. Prognostic impact of toll-like receptors gene polymorphism on outcome of COVID-19 pneumonia: A case-control study. Clin Immunol 2022; 235:108929. [PMID: 35063671 PMCID: PMC8767970 DOI: 10.1016/j.clim.2022.108929] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 11/28/2021] [Accepted: 01/13/2022] [Indexed: 12/11/2022]
Abstract
Toll-like receptor 3 (TLR3) and TLR7 genes are involved in the host immune response against viral infections including SARS-COV-2. This study aimed to investigate the association between the TLR3(rs3775290) and TLR7(rs179008) polymorphisms with the prognosis and susceptibility to COVID-19 pneumonia accompanying SARS-COV-2 infection. This case-control study included 236 individuals: 136 COVID-19 pneumonia patients and 100 age and sex-matched controls. Two polymorphisms (TLR3 rs3775290 and TLR7 rs179008) were genotyped by allelic discrimination through TaqMan real-time PCR. This study also investigated predictors of mortality in COVID-19 pneumonia through logistic regression. The mutant ‘T/T' genotypes and the ‘T' alleles of TLR3(rs3775290) and TLR7(rs179008) polymorphisms were significantly associated with increased risk of COVID-19 pneumonia. This study did not report association between the mutant ‘T/T' genotypes of TLR3(rs3775290) and TLR7(rs179008) and the disease outcome. In multivariate analysis, the independent predictors of mortality in COVID-19 pneumonia were male sex, SPO2 ≤ 82%, INR > 1, LDH ≥ 1000 U/l, and lymphocyte count<900/mm3 (P < 0.05).
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8
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Li X, Li Q, Ruan W. Identification of Avian Toll-Like Receptor 3 and 7 and Analysis of Gene Variation Sites. BRAZILIAN JOURNAL OF POULTRY SCIENCE 2022. [DOI: 10.1590/1806-9061-2020-1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- X Li
- Beijing University of Agriculture, China
| | - Q Li
- Beijing University of Agriculture, China
| | - W Ruan
- Beijing University of Agriculture, China
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9
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Abstract
Toll-like receptors were discovered as proteins playing a crucial role in the dorsoventral patterning during embryonic development in the Drosophila melanogaster (D. melanogaster) almost 40 years ago. Subsequently, further research also showed a role of the Toll protein or Toll receptor in the recognition of Gram-positive bacterial and fungal pathogens infecting D. melanogaster. In 1997, the human homolog was reported and the receptor was named the Toll-like receptor 4 (TLR4) that recognizes lipopolysaccharide (LPS) of the Gram-negative bacteria as a pathogen-associated molecular pattern (PAMP). Identification of TLR4 in humans filled the long existing gap in the field of infection and immunity, addressing the mystery surrounding the recognition of foreign pathogens/microbes by the immune system. It is now known that mammals (mice and humans) express 13 different TLRs that are expressed on the outer cell membrane or intracellularly, and which recognize different PAMPs or microbe-associated molecular patterns (MAMPs) and death/damage-associated molecular patterns (DAMPs) to initiate the protective immune response. However, their dysregulation generates profound and prolonged pro-inflammatory immune responses responsible for different inflammatory and immune-mediated diseases. This chapter provides an overview of TLRs in the control of the immune response, their association with different diseases, including TLR single nucleotide polymorphisms (SNPs), interactions with microRNAs (miRs), use in drug development and vaccine design, and expansion in neurosciences to include pain, addiction, metabolism, reproduction, and wound healing.
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Affiliation(s)
- Vijay Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - James E Barrett
- Drexel University College of Medicine, Philadelphia, PA, USA.
- Department of Neural Sciences, Centre for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
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Altomare A, Corrado A, Maruotti N, Cici D, Cantatore FP. Hcv and Autoimmunity in Rheumatic Diseases. Curr Rheumatol Rev 2021; 18:101-107. [PMID: 34387165 DOI: 10.2174/1573397117666210812141524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022]
Abstract
HCV is a global health problem affecting mainly the liver and often characterized by extrahepatic manifestions mediated by autoimmune reactions. Among these, arthritis and arthralgia are most frequent, as well as the presence of cryoglobulinemia that may induce vasculitis, and sicca syndrome. Thus, HCV appears to be a trigger for autoimmune response as demonstrated by the finding of autoantibody in a high percentage of serum of these patients. Therefore, it is important that clinicians recognize these autoimmune manifestations as symptoms due to an autoimmune activity triggered by HCV, in order to give the correct diagnosis and start an effective therapy strategy. Therefore, clinical examination, searching of markers of infection as well as autoantibody patterns should be performed to make a correct differential diagnosis. The treatment should be based on antiviral drugs associated to immunosuppressive drugs according to autoimmune manifestations.
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Affiliation(s)
- Alberto Altomare
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Addolorata Corrado
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Nicola Maruotti
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Daniela Cici
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
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Shaltiel T, Zheng S, Siderides C, Gleeson EM, Carr J, Pletcher ER, Cohen NA, Golas BJ, Magge DR, Labow DM, Branch AD, Sarpel U. Hepatitis C-positive Black patients develop hepatocellular carcinoma at earlier stages of liver disease and present with a more aggressive phenotype. Cancer 2021; 127:1395-1406. [PMID: 33629759 PMCID: PMC8084866 DOI: 10.1002/cncr.33377] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/28/2020] [Accepted: 09/07/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND In the United States, mortality after a diagnosis of hepatocellular carcinoma (HCC) is higher in patients who are Black than in patients of other racial groups. The objective of this study was to clarify factors contributing to this disparity by analyzing liver and tumor characteristics in patients with HCC who have a history of hepatitis C virus (HCV) infection. METHODS Records of patients with HCV and HCC at the authors' institution from 2003 to 2018 were retrospectively reviewed. Race and ethnicity were self-identified. Imaging, laboratory, and pathologic features were compared between Black and non-Black cohorts. RESULTS Among 1195 individuals with HCC, 390 identified as Black. At the time of HCC diagnosis, Black patients had better liver function, as measured by Child-Pugh score, Model of End-Stage Liver Disease score, histology of nontumor tissue, and fibrosis-4 (FIB-4) score (all P < .05). FIB-4 scores were <3.25 in 31% of Black patients. In addition, Black patients had less early stage HCC (20.2% vs 32.3%; P < .05), larger tumors (median [interquartile range]: 3.5 cm [2.2-6.2 cm] vs 3.1 cm [2.1-5.1 cm]; P < .01), more multiple tumors (median, [interquartile range]: 1 tumor [1-3 tumors] vs 1 tumor [1-2 tumors]; P = .03), more poorly differentiated tumors (30.3% vs 20.5%; P < .05), and more microvascular invasion (67.2% vs 56.5%; P < .05). CONCLUSIONS Black patients with HCV exposure develop HCC at earlier stages of liver disease than members of other racial groups. Nearly one-third would not qualify for HCC screening using the common FIB-4 cirrhosis threshold. Practice guidelines that stress HCC surveillance for cirrhotic patients with HCV may need to be revised to be more inclusive for Black patients. In addition, tumors in Black patients carry worse prognostic features, and molecular studies are needed to characterize their biologic properties.
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Affiliation(s)
- Tali Shaltiel
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Serena Zheng
- Icahn School of Medicine at Mount Sinai, New York, NY
| | | | | | - Jacquelyn Carr
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Eric R. Pletcher
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Noah A. Cohen
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | | | - Deepa R. Magge
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Daniel M. Labow
- Department of Surgery, Division of Surgical Oncology, New York, NY
| | - Andrea D. Branch
- Department of Medicine, Division of Liver Diseases, New York, NY
| | - Umut Sarpel
- Department of Surgery, Division of Surgical Oncology, New York, NY
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The Arg753Gln Polymorphism of Toll-Like Receptor 2 Has a Lower Occurrence in Patients with Syphilis, Suggesting Its Protective Effect in Czech and Slovak Individuals. Infect Immun 2020; 89:IAI.00503-20. [PMID: 33077622 DOI: 10.1128/iai.00503-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/07/2020] [Indexed: 11/20/2022] Open
Abstract
Syphilis is a bacterial infection caused by Treponema pallidum subsp. pallidum Infection with T. pallidum subsp. pallidum and its dissemination lead to the synthesis of proinflammatory cytokines triggered by the interaction of bacterial lipoproteins with Toll-like receptor 2 (TLR2). TLR2 contains several nonsynonymous single-nucleotide polymorphisms that may impact the activation of its signaling cascade and alter the responsiveness to, or the course of, various infectious diseases, including those caused by pathogenic spirochetes. To investigate whether TLR2 polymorphism may influence susceptibility to syphilis, 221 healthy individuals with no history of syphilis (controls) and 137 patients diagnosed with syphilis (cases) were screened for the presence of the Arg753Gln polymorphism in the TLR2 gene (2258G→A; rs5743708). The Arg753Gln variant occurs at a significantly lower frequency in syphilis patients (4 of 137 [3%]) than in controls (24 of 221 [10.9%]). These data suggest that TLR2 Arg753Gln may protect from the development of syphilis due to reduced signaling.
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Qaradakhi T, Gadanec LK, McSweeney KR, Abraham JR, Apostolopoulos V, Zulli A. The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease. Nutrients 2020; 12:E2847. [PMID: 32957558 PMCID: PMC7551180 DOI: 10.3390/nu12092847] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.
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Affiliation(s)
- Tawar Qaradakhi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia; (L.K.G.); (K.R.M.); (J.R.A.); (V.A.); (A.Z.)
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Liu G, Gack MU. Distinct and Orchestrated Functions of RNA Sensors in Innate Immunity. Immunity 2020; 53:26-42. [PMID: 32668226 PMCID: PMC7367493 DOI: 10.1016/j.immuni.2020.03.017] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 03/07/2020] [Accepted: 03/07/2020] [Indexed: 12/21/2022]
Abstract
Faithful maintenance of immune homeostasis relies on the capacity of the cellular immune surveillance machinery to recognize "nonself", such as the presence of pathogenic RNA. Several families of pattern-recognition receptors exist that detect immunostimulatory RNA and then induce cytokine-mediated antiviral and proinflammatory responses. Here, we review the distinct features of bona fide RNA sensors, Toll-like receptors and retinoic-acid inducible gene-I (RIG-I)-like receptors in particular, with a focus on their functional specificity imposed by cell-type-dependent expression, subcellular localization, and ligand preference. Furthermore, we highlight recent advances on the roles of nucleotide-binding oligomerization domain (NOD)-like receptors and DEAD-box or DEAH-box RNA helicases in an orchestrated RNA-sensing network and also discuss the relevance of RNA sensor polymorphisms in human disease.
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Affiliation(s)
- GuanQun Liu
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA
| | - Michaela U Gack
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA.
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El Aggan H, Farahat N, El Deeb N, Zeid A, El-Shendidi A. Peripheral blood and hepatic Toll-like receptor 7 expression and interferon lambda 1 levels in chronic hepatitis C: Relation to virus replication and liver injury. Microb Pathog 2019; 131:65-74. [PMID: 30926417 DOI: 10.1016/j.micpath.2019.03.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 03/23/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Toll-like receptor 7 (TLR7) can recognize single-stranded RNA viruses like hepatitis C virus (HCV) with subsequent induction of different interferon (IFN) types including IFN lambda (IFNL), which activate an immediate anti-viral response. However, the role of TLR7 in inflammation and fibrosis, characteristics of HCV-induced liver injury, is still controversial. The present work was designed to investigate the potential role of TLR7 and IFNL1 in chronic hepatitis C (CHC) in relation to viral replication and liver injury. METHODS Forty two treatment-naïve patients with CHC and 20 healthy subjects were enrolled in the study. TLR7 expression on peripheral blood CD14+ monocytes was studied by color flow cytometry and the frequency of TLR7+CD14+ cells was expressed as percentage of total monocyte count. Quantification of IFNL1 levels in serum was determined using enzyme-linked immunosorbant assay. Liver biopsies were examined for assessment of histological activity grade (A0-A3) and fibrosis stage (F0-F4) according to METAVIR scoring system as well as steatosis grade. Immunohistochemical staining was performed using human antibodies against TLR7 and IFNL1 and was scored semi-quantitatively (score 0-3). Hepatic expression of TLR7 and IFNL1 was further classified using a two-grade scale as low expression (score 0 or 1) and high expression (score 2 or 3). RESULTS Percentages of circulating TLR7+CD14+ monocytes and serum IFNL1 levels were significantly higher in patients with CHC than in healthy controls (P = 0.025 and P < 0.001 respectively) and were positively correlated with corresponding hepatic TLR7 and IFNL1 expression (P < 0.001 and P = 0.010 respectively). Significantly lower peripheral blood and hepatic TLR7 expression and IFNL1 levels were found in patients with viral loads between 200,000-600,000 IU/ml and >600,000 IU/ml than in those with viral load <200,000 IU/ml (P < 0.05), in patients with severe necroinflammation than in those with mild-to-moderate necroinflammation (P < 0.05) and in patients with advanced fibrosis than in those with early fibrosis (P < 0.01). Also, changes in TLR7 expression and IFNL1 production in peripheral blood and the liver were inversely correlated with serum levels of aspartate and alanine aminotransferases (P < 0.05) and HCV RNA (P < 0.01), histological activity grade (P < 0.01) and fibrosis stage (P < 0.01). By plotting receiver operating characteristics (ROC) curve, serum IFNL1 showed higher sensitivity and specificity than percentages of circulating TLR7+CD14+ monocytes in discriminating patients with CHC according to the severity of hepatic necroinflammation (area under the curve (AUC) = 0.901 vs. 0.816 respectively) and fibrosis (AUC = 0.971 vs. 0.825 respectively) at a cut-off value of 44.75 pg/ml and 10.25% respectively. CONCLUSIONS TLR7 activation and IFNL1 production in CHC may play an important role in controlling viral replication and limiting hepatic inflammation and fibrosis and their downregulation may result in viral persistence and disease progression. The immunoregulatory role of TLR7-IFNL1 pathway in the pathogenesis of chronic HCV infection should be further studied. Clinical trials with a large number of patients are needed to assess the usefulness of serum IFNL1 as a potential biomarker for severity of liver injury in chronic HCV infection and other liver diseases.
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Affiliation(s)
- Hoda El Aggan
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt.
| | - Nahla Farahat
- Department of Clinical and Chemical Pathology, Faculty of Medicine, University of Alexandria, Egypt
| | - Nevine El Deeb
- Department of Pathology, Faculty of Medicine, University of Alexandria, Egypt
| | - Ahmed Zeid
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt
| | - Assem El-Shendidi
- Department of Internal Medicine (Hepatobiliary Unit), Faculty of Medicine, University of Alexandria, Egypt
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Mukherjee S, Huda S, Sinha Babu SP. Toll-like receptor polymorphism in host immune response to infectious diseases: A review. Scand J Immunol 2019; 90:e12771. [PMID: 31054156 DOI: 10.1111/sji.12771] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 04/20/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022]
Abstract
Immunopolymorphism is considered as an important aspect behind the resistance or susceptibility of the host to an infectious disease. Over the years, researchers have explored many genetic factors for their role in immune surveillance against infectious diseases. Polymorphic characters in the gene encoding Toll-like receptors (TLRs) play profound roles in inducing differential immune responses by the host against parasitic infections. Protein(s) encoded by TLR gene(s) are immensely important due to their ability of recognizing different types of pathogen associated molecular patterns (PAMPs). This study reviews the polymorphic residues present in the nucleotide or in the amino acid sequence of TLRs and their influence on alteration of inflammatory signalling pathways promoting either susceptibility or resistance to major infectious diseases, including tuberculosis, leishmaniasis, malaria and filariasis. Population-based studies exploring TLR polymorphisms in humans are primarily emphasized to discuss the association of the polymorphic residues with the occurrence and epidemiology of the mentioned infectious diseases. Principal polymorphic residues in TLRs influencing immunity to infection are mostly single nucleotide polymorphisms (SNPs). I602S (TLR1), R677W (TLR2), P554S (TLR3), D299G (TLR4), F616L (TLR5), S249P (TLR6), Q11L (TLR7), M1V (TLR8), G1174A (TLR9) and G1031T (TLR10) are presented as the major influential SNPs in shaping immunity to pathogenic infections. The contribution of these SNPs in the structure-function relationship of TLRs is yet not clear. Therefore, molecular studies on such polymorphisms can improve our understanding on the genetic basis of the immune response and pave the way for therapeutic intervention in a more feasible way.
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Affiliation(s)
| | - Sahel Huda
- Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, India
| | - Santi P Sinha Babu
- Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, India
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17
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Shackel NA, Patel K. Viral hepatitis. GENOMIC AND PRECISION MEDICINE 2019:155-165. [DOI: 10.1016/b978-0-12-801496-7.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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El-Bendary M, Neamatallah M, Elalfy H, Besheer T, Elkholi A, El-Diasty M, Elsareef M, Zahran M, El-Aarag B, Gomaa A, Elhammady D, El-Setouhy M, Hegazy A, Esmat G. The association of single nucleotide polymorphisms of Toll-like receptor 3, Toll-like receptor 7 and Toll-like receptor 8 genes with the susceptibility to HCV infection. Br J Biomed Sci 2018; 75:175-181. [PMID: 29947302 DOI: 10.1080/09674845.2018.1492186] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 06/08/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) are linked with functional modification of cytokine responses. In chronic hepatitis C virus (HCV) infection, studies of TLR polymorphisms have primarily targeted receptor pathways implicated in viral immune responses. We hypothesized that one or more variant(s) of TLR3, TLR7 and TLR8 are associated with different outcomes of HCV infection. MATERIALS & METHODS A total of 3368 subjects from 850 families were recruited and divided into three main groups categorized as chronic HCV CHC spontaneous viral clearance (SVC), and controls. All individuals were genotyped for three SNPs for TLR3, two SNPs for TLR7, and two SNPs for TLR8 using allelic discrimination real-time PCR. RESULTS Carriage of the C allele in three SNPs of TLR3 (rs3775290, rs3775291, and rs5743312), the C allele in TLR7 (rs3853839) in females only, and the C allele in TLR8 (rs3764879) in males only were significantly higher in SVC group than CHC group (P < 0.001), while carriage of the T allele in TLR7 (rs179008) in females only and the A allele in TLR8 (rs3764880) in both males and females were significantly higher in CHC infection more than SVC group (P < 0.001). CONCLUSION The C allele is protective of HCV in TLR3, TLR7 (rs3853839) in females only, and TLR8 (rs3764879) in males only, while risk of infection is linked to the T allele in TLR7 (rs179008) in females only and the A allele in TLR8 (rs3764880) in both sexes.
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Affiliation(s)
- M El-Bendary
- a Tropical Medicine and Hepatology Department, Faculty Of Medicine , Mansoura University , Mansoura , Egypt
| | - M Neamatallah
- b Medical Biochemistry Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - H Elalfy
- a Tropical Medicine and Hepatology Department, Faculty Of Medicine , Mansoura University , Mansoura , Egypt
| | - T Besheer
- a Tropical Medicine and Hepatology Department, Faculty Of Medicine , Mansoura University , Mansoura , Egypt
| | - A Elkholi
- c Gastroenterology Department , Health Insurance Hospital , Mansoura , Egypt
| | - M El-Diasty
- a Tropical Medicine and Hepatology Department, Faculty Of Medicine , Mansoura University , Mansoura , Egypt
| | - M Elsareef
- d Biochemistry Division, Chemistry Department, Faculty of Science , Menoufia University , Shebin El-Koom , Egypt
| | - M Zahran
- e Chemistry Department, Faculty of Science , Menoufia University , Shebin El-Koom , Egypt
| | - B El-Aarag
- d Biochemistry Division, Chemistry Department, Faculty of Science , Menoufia University , Shebin El-Koom , Egypt
| | - A Gomaa
- f Zoology Department, Faculty of Science , Alazhar University , Cairo , Egypt
| | - D Elhammady
- a Tropical Medicine and Hepatology Department, Faculty Of Medicine , Mansoura University , Mansoura , Egypt
| | - M El-Setouhy
- g Department of Community, Environmental, and Occupational Medicine, Faculty of Medicine , Ain-Shams University, Cairo, Egypt; Substance Abuse Research Center (SARC), Jazan University , Jazan , Kingdom of Saudi Arabia
| | - A Hegazy
- h Internal Medicine Department, Faculty of Medicine , Alazhar University , Cairo , Egypt
| | - G Esmat
- i Endemic Medicine and Endemic Hepatogastroenterology Department, Faculty of Medicine , Cairo University , Cairo , Egypt
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Hamdy S, Osman AM, Zakaria ZA, Galal I, Sobhy M, Hashem M, Allam WR, Abdel-Samiee M, Rewisha E, Waked I, Abdelwahab SF. Association of Toll-like receptor 3 and Toll-like receptor 9 single-nucleotide polymorphisms with hepatitis C virus persistence among Egyptians. Arch Virol 2018; 163:2433-2442. [PMID: 29860675 DOI: 10.1007/s00705-018-3893-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 05/15/2018] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) give the innate immune system a considerable specificity for a large range of pathogens. TLR3 detects dsRNA of viruses while TLR9 recognizes bacterial and viral unmethylated CpG motifs. This study examined whether there is a potential association between single-nucleotide polymorphisms (SNPs) in the TLR3.rs3775290 (c.1377C/T), TLR9.rs5743836 (-1237T→C) and TLR9.rs352140 (G2848A) genes and HCV infection among Egyptian patients and healthcare workers (HCWs). We enrolled 546 subjects (409 HCWs and 137 patients) divided into four groups: group 1 included 265 seronegative, aviremic subjects; group 2 included 25 seronegative, viremic subjects; group 3 included 87 subjects with spontaneously resolved HCV infection; and group 4 included 169 chronic HCV patients. All subjects were genotyped for TLR3.rs3775290, TLR9.rs5743836 and TLR9.rs352140 SNPs by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. TLR3.rs3775290 "CC" genotype was associated with chronic HCV infection, where there was a significantly greater frequency of this genotype among chronic patients when compared to subjects with spontaneously resolved infection (63.9% vs. 51.9%; p = 0.033; OR = 1.639 and 95% CI = 0.94-2.84). However, this SNP did not correlate with the HCV RNA load among the chronic subjects (p > 0.05). There was no significant difference in TLR9.rs5743836 and TLR9.rs352140 genotype distribution between groups (p > 0.05). Lack of association between the three SNPs was found, as the three SNPs are located on two different chromosomes. In conclusion, the TLR3.rs3775290 "CC" genotype was associated with HCV chronicity, while the TLR9 gene may not play a major role in HCV infection.
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Affiliation(s)
- Shaimaa Hamdy
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Ahmed M Osman
- Department of Zoology, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Zainab A Zakaria
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Biomedical Research Laboratory, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Iman Galal
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Maha Sobhy
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Mohamed Hashem
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Walaa R Allam
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Centre for Genomics, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Eman Rewisha
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Imam Waked
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Sayed F Abdelwahab
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt.
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511, Egypt.
- Department of Microbiology, Taif Faculty of Pharmacy, Al-Haweiah, PO Box 888, Taif, 21974, Kingdom of Saudi Arabia.
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Buschow SI, Biesta PJ, Groothuismink ZMA, Erler NS, Vanwolleghem T, Ho E, Najera I, Ait-Goughoulte M, de Knegt RJ, Boonstra A, Woltman AM. TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands. Antiviral Res 2018; 157:27-37. [PMID: 29964062 DOI: 10.1016/j.antiviral.2018.06.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 06/21/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023]
Abstract
TLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance. Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054). Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.
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Affiliation(s)
- Sonja I Buschow
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Paula J Biesta
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Zwier M A Groothuismink
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Nicole S Erler
- Department of Biostatistics, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands; Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Erwin Ho
- Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Isabel Najera
- Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Switzerland
| | - Malika Ait-Goughoulte
- Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Switzerland
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Andrea M Woltman
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, The Netherlands.
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Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol 2018; 59:391-412. [PMID: 29730580 PMCID: PMC7106078 DOI: 10.1016/j.intimp.2018.03.002] [Citation(s) in RCA: 454] [Impact Index Per Article: 64.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 02/07/2023]
Abstract
The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.
TLRs are first described PRRs that revolutionized the biology of host-pathogen interaction and immune response The discovery of different TLRs in humans proved milestone in the field of innate immunity and inflammation The pattern of expression of all the TLRs expressed by human immune cells An association of various TLR SNPs with different inflammatory diseases Currently available drugs or vaccines based on TLRs and their future in drug targeting along with the role in reproduction, and regeneration
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Nurjadi D, Heeg K, Weber ANR, Zanger P. Toll-like receptor 9 (TLR-9) promotor polymorphisms and gene expression are associated with persistent Staphylococcus aureus nasal carriage. Clin Microbiol Infect 2018; 24:1210.e7-1210.e12. [PMID: 29458158 DOI: 10.1016/j.cmi.2018.02.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/21/2017] [Accepted: 02/08/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Toll-like receptor (TLR) 9 could have importance in human Staphylococcus aureus immunity, but population-level evidence for this hypothesis is missing. METHODS We phenotyped S. aureus nasal carriage of 603 volunteers using four consecutive swabs, genotyped TLR9 promotor variants in 106 persistent carriers and 219 noncarriers, measured TLR9-mRNA expression in whole blood after stimulation with viable S. aureus and studied mutual associations of carriage, transcriptional activity and single nucleotide polymorphisms while accounting for sex and hormone contraceptive use (HCU). RESULTS The -1486 (rs187084) and -1237 (rs5743836) CT haplotype was more common in noncarriers (185/438, 42%) than in carriers (63/212, 30%), with the TT haplotype showing a reverse association (noncarriers, 180/438, 41%; carriers 117/212, 55%) (χ2 p 0.001). Mean TLR9 mRNA expression in whole blood was higher in noncarriers (ratiocarriers/noncarriers 0.63; 95% confidence interval, 0.43-0.92; p 0.017). A duplication of TLR9 transcriptional activity lowered the odds of persistent S. aureus carriage by 37% in the overall group (odds ratio = 0.63; 95% confidence interval, 0.42-0.94; p 0.022) and by 54% in women (odds ratio = 0.46; 95% confidence interval, 0.23-0.90; p 0.023). Promotor haplotype and HCU had a combined effect on TLR9 transcription (interaction model): women in the TT (risk) haplotype/HCU- stratum (baseline) had lower mRNA levels than women in the CT (protective) haplotype/HCU- (ratio 1.92; p 0.055), the CT haplotype/HCU+ (ratio 2.02; p 0.032) and the TT haplotype/HCU+ (ratio 2.59; p < 0.004) strata. No such associations were observed in men. CONCLUSIONS We provide evidence that TLR9 affects human S. aureus immunity and present potential explanations for differences according to sex in S. aureus colonization and infection.
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Affiliation(s)
- D Nurjadi
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospitals, Heidelberg, Germany; Institute of Tropical Medicine, University Hospitals, Tübingen, Germany
| | - K Heeg
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospitals, Heidelberg, Germany
| | - A N R Weber
- Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard-Karls-Universität, Tübingen, Germany
| | - P Zanger
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospitals, Heidelberg, Germany; Heidelberg Institute of Public Health, University Hospitals, Ruprecht-Karls-Universität, Heidelberg, Germany.
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Toll like receptor7 polymorphisms in relation to disease susceptibility and progression in Chinese patients with chronic HBV infection. Sci Rep 2017; 7:12417. [PMID: 28963470 PMCID: PMC5622102 DOI: 10.1038/s41598-017-12698-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/13/2017] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) play a key role in innate and adaptive immunity, protecting the host from viral pathogens. We studied the effect of TLR7 polymorphisms on disease susceptibility and progression of chronic hepatitis B (CHB) infection in Chinese adults. Blood samples were taken from 612 patients with confirmed CHB, hepatitis B virus (HBV)-related liver cirrhosis (LC) or hepatocellular carcinoma (HCC) and 293 controls. TLR7 polymorphisms (rs179010-C > T, rs2074109-T > C, and rs179009-A > G) were analyzed by PCR-based sequencing. A significantly higher frequency of TLR7 rs179010 C allele was found in male CHB patients than in controls (74.8% vs 59.5%, P = 0.002). The frequency of rs179009 G allele was markedly increased with disease progression when male patients with CHB, LC and HCC were compared (P = 0.012). The haplotype CTA was significantly associated with an increased susceptibility to CHB among male patients (P = 0.000). Frequency of the haplotype CTG was higher in male patients with HCC than CHB (P = 0.005). No such differences in these allele frequencies were found between female patients and controls. Our results indicated that TLR7 polymorphisms play an important role in disease susceptibility and the progression of CHB infections in Chinese adults, and may partly explain the high incidence of HBV related diseases in Chinese men.
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Tartey S, Takeuchi O. Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells. Int Rev Immunol 2017; 36:57-73. [PMID: 28060562 DOI: 10.1080/08830185.2016.1261318] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The innate immune system deploys a variety of pattern-recognition receptors (PRRs) which include Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors to detect the invasion of pathogens and initiate protective responses. The intercellular and intracellular orchestration of signals from different PRRs, their endogenous or microbial ligands and accessory molecules determine the stimulatory or inhibitory responses. Progressing over the last two decades, considerable research on the molecular mechanisms underlying host-pathogen interactions has led to a paradigm shift of our understanding of TLR signaling in the innate immune system. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. In this review, we discuss the recent advances in TLR signaling cross talks and the mechanism of pathogen recognition with special emphasis on the role of TLRs in tumor immunity and TLR-targeted therapeutics.
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Affiliation(s)
- Sarang Tartey
- a Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University , Kawara-Cho, Sakyo-Ku, Kyoto , Japan.,b AMED-CREST, Japan Agency for Medical Research and Development , Kyoto , Japan
| | - Osamu Takeuchi
- a Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University , Kawara-Cho, Sakyo-Ku, Kyoto , Japan.,b AMED-CREST, Japan Agency for Medical Research and Development , Kyoto , Japan
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26
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Zhang Y, El-Far M, Dupuy FP, Abdel-Hakeem MS, He Z, Procopio FA, Shi Y, Haddad EK, Ancuta P, Sekaly RP, Said EA. HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses. Sci Rep 2016; 6:29447. [PMID: 27385120 PMCID: PMC4935957 DOI: 10.1038/srep29447] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 06/20/2016] [Indexed: 02/08/2023] Open
Abstract
The innate and adaptive immune systems fail to control HCV infection in the majority of infected individuals. HCV is an ssRNA virus, which suggests a role for Toll-like receptors (TLRs) 7 and 8 in initiating the anti-viral response. Here we demonstrate that HCV genomic RNA harbours specific sequences that initiate an anti-HCV immune response through TLR7 and TLR8 in various antigen presenting cells. Conversely, HCV particles are detected by macrophages, but not by monocytes and DCs, through a TLR7/8 dependent mechanism; this leads to chloroquine sensitive production of pro-inflammatory cytokines including IL-1β, while the antiviral type I Interferon response is not triggered in these cells. Antibodies to DC-SIGN, a c-type lectin selectively expressed by macrophages but not pDCs or mDCs, block the production of cytokines. Novel anti-HCV vaccination strategies should target the induction of TLR7/8 stimulation in APCs in order to establish potent immune responses against HCV.
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Affiliation(s)
- Yuwei Zhang
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA
| | - Mohamed El-Far
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Franck P Dupuy
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA.,Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Mohamed S Abdel-Hakeem
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - Zhong He
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA
| | - Francesco Andrea Procopio
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA
| | - Yu Shi
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA
| | - Elias K Haddad
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA
| | - Petronela Ancuta
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada
| | - Rafick-Pierre Sekaly
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Vaccine and Gene Therapy Institute-Florida (VGTI-FL), Port Saint Lucie, Florida 3498, USA.,Case Western Reserve University, Cleveland, Ohio, USA
| | - Elias A Said
- Centre de recherche du centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital Saint-Luc, Québec H2X 0A9, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.,Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, the Sultanate of Oman
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27
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Xue XX, Gong JM, Tang SD, Gao CF, Wang JJ, Cai L, Wang J, Yu RB, Peng ZH, Fan NJ, Wang CJ, Zhu J, Zhang Y. Single nucleotide polymorphisms of toll-like receptor 7 in hepatitis C virus infection patients from a high-risk chinese population. Inflammation 2015; 38:142-51. [PMID: 25218653 DOI: 10.1007/s10753-014-0016-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Hepatitis C virus (HCV) infection varies in the outcomes depending on both viral and host factors. This study aims to investigate the associations of three single nucleotide polymorphisms (SNPs) of Toll-like receptor 7 (TLR7), rs179016, rs5743733, and rs1634323, with susceptibility to HCV infection and clearance. The three SNPs were genotyped in a high-risk Chinese population, including 444 HCV spontaneous clearance cases, 732 persistent infection cases, and 1107 healthy controls. The G allele of rs1634323 was related to the protection from persistent infection among females (dominant model: odds ratio (OR) = 0.558, 95 % confidence interval (CI) = 0.348-0.894, P = 0.015). This protective effect was more evident in blood donation and HCV non-1 genotype-infected subgroups (all P < 0.05). The carriage of rs179016 C allele was more prone to develop persistent infection (OR = 1.444, 95 % CI = 1.096-1.903, P = 0.009) in males, and the risk effect remained significant among older (>50 years), hemodialysis (HD), and HCV-1 and HCV non-1 genotypes-infected subjects (all P < 0.05). Haplotype analyses showed that CCA haplotype among females was correlated with the elevated risk of HCV susceptibility while the carriage of GGA was more prone to be infected with HCV and CCA was more likely to develop persistent infection (all P < 0.05) among males. Our results first demonstrated that the carriage of rs179016 C allele had a negative effect on spontaneous clearance of HCV among males while rs1634323 G allele conferred a protective effect against persistent infection among female subjects.
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Affiliation(s)
- Xing-Xin Xue
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China
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28
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Arslan S, Engin A, Özbilüm N, Bakır M. Toll-like receptor 7 Gln11Leu, c.4-151A/G, and +1817G/T polymorphisms in Crimean Congo hemorrhagic fever. J Med Virol 2015; 87:1090-5. [DOI: 10.1002/jmv.24174] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 01/13/2023]
Affiliation(s)
- Serdal Arslan
- Department of Medical Biology; Faculty of Medicine; Cumhuriyet University; Sivas Turkey
| | - Aynur Engin
- Department of Molecular Biology and Genetic; Faculty of Science; Cumhuriyet University; Sivas Turkey
| | - Nil Özbilüm
- Departments of Infectious Diseases and Clinical Microbiology; Cumhuriyet University, School of Medicine; 58140 Sivas Turkey
| | - Mehmet Bakır
- Department of Molecular Biology and Genetic; Faculty of Science; Cumhuriyet University; Sivas Turkey
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29
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Ruan W, An J, Wu Y. Polymorphisms of chicken TLR3 and 7 in different breeds. PLoS One 2015; 10:e0119967. [PMID: 25781886 PMCID: PMC4364021 DOI: 10.1371/journal.pone.0119967] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 01/18/2015] [Indexed: 11/19/2022] Open
Abstract
Toll-like receptors (TLRs) mediate immune responses via the recognition of pathogen-associated molecular patterns (PAMPs), thus playing important roles in host defense. Among the chicken (Ch) TLR family, ChTLR3 and 7 have been shown to recognize viral RNA. In our earlier studies, we have reported polymorphisms of TLR1, 2, 4, 5, 15 and 21. In the present study, we amplified TLR3 and 7 genes from different chicken breeds and analyzed their sequences. We identified 7 amino acid polymorphism sites in ChTLR3 with 6 outer part sites and 1 inner part site, and 4 amino acid polymorphism sites in ChTLR7 with 3 outer part sites and 1 inner part site. These results demonstrate that ChTLR genes are polymorphic among different chicken breeds, suggesting a varied resistance across numerous chicken breeds. This information might help improve chicken health by breeding and vaccination.
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Affiliation(s)
- Wenke Ruan
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
- * E-mail: (WR); (YW)
| | - Jian An
- College of Animal Science and Technology, Beijing University of Agriculture, Beijing 102206, China
| | - Yanhua Wu
- Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
- * E-mail: (WR); (YW)
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30
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Latella G, Rogler G, Bamias G, Breynaert C, Florholmen J, Pellino G, Reif S, Speca S, Lawrance IC. Results of the 4th scientific workshop of the ECCO (I): pathophysiology of intestinal fibrosis in IBD. J Crohns Colitis 2014; 8:1147-1165. [PMID: 24731838 DOI: 10.1016/j.crohns.2014.03.008] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 03/10/2014] [Accepted: 03/14/2014] [Indexed: 02/08/2023]
Abstract
The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of intestinal fibrosis, to identify useful markers and imaging modalities of fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of fibrosis. The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of intestinal fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of intestinal fibrosis and provides a framework for future research.
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Affiliation(s)
- Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy.
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hopsital of Zurich, Zurich, Switzerland
| | - Giorgos Bamias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Christine Breynaert
- Department of Immunology and Microbiology, Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium; Department of Clinical and Experimental Medicine, Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Institute of Clinical Medicine, Artic University of Norway and University Hospital of Northern Norway, Tromsø, Norway
| | - Gianluca Pellino
- General Surgery Unit, Second University of Naples, Naples, Italy
| | - Shimon Reif
- Department of Pediatrics, Hadassah Medical Center, Jerusalem, Israel
| | - Silvia Speca
- National Institute of Health and Medical Research-INSERM, Unit U995, Lille, France
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Fremantle Hospital, WA, Australia; University Department of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, WA, Australia
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31
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Yue M, Gao CF, Wang JJ, Wang CJ, Feng L, Wang J, Yu RB, Peng ZH, Xue XX, Cai L, Fan NJ, Zhang Y, Deng XZ. Toll-like receptor 7 variations are associated with the susceptibility to HCV infection among Chinese females. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2014; 27:264-270. [PMID: 25108054 DOI: 10.1016/j.meegid.2014.07.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Revised: 07/20/2014] [Accepted: 07/22/2014] [Indexed: 12/18/2022]
Abstract
Toll-like receptors 7 (TLR7) play a crucial role in provoking an immune response in HCV infection. We aimed to investigate whether single nucleotide polymorphisms (SNPs) of TLR7, including rs179009, rs179010 and rs179012, affect the outcomes of HCV infection among the Chinese population. A total of 1767 Chinese Han individuals were enrolled. The distribution of SNP frequencies among three groups with different outcomes of HCV infection was assessed, including healthy controls, cases with spontaneous clearance and cases with viral persistence. Then TLR7 mRNA expression and the production of IFN-α and IL-6 after TLR7 agonist Imiquimod stimulation in vitro were determined. Our results suggested that rs179009 GG genotype was significantly associated with a higher risk of the susceptibility to HCV infection among female subjects (OR=2.42, 95% CI=1.24-4.71, P=0.01). Haplotype GCG was significantly associated with a high risk for HCV susceptibility (OR=1.50, 95% CI=1.11-2.03, P=0.01) as compared with the reference haplotype ACG among females. In the functional research of rs179009, a lower IFN-α level was observed in GG genotype than in AA genotype (P=0.032). Our data indicate that TLR7 rs179009 GG genotype and haplotype GCG were associated with an increased risk of the susceptibility to HCV infection among Chinese females, which may be due to the impaired IFN-α response.
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Affiliation(s)
- Ming Yue
- School of Life Science and Technology, Jiangsu Province Hospital, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China; Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Chun-fang Gao
- Department of Anal-Colorectal Surgery, The 150th Central Hospital of Chinese People's Liberation Army, No. 2 Huaxia West Road, Jianxi District, Luoyang 471031, Henan, China
| | - Jia-jia Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Chang-jun Wang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Le Feng
- Department of Infection and Immunity, Yixing People's Hospital, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, China
| | - Jie Wang
- School of Nursing, Nanjing Medical University, No. 140 Hanzhong Road, Nanjing 210029, China
| | - Rong-bin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Zhi-hang Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Xing-xin Xue
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Li Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China
| | - Nai-jun Fan
- Department of Anal-Colorectal Surgery, The 150th Central Hospital of Chinese People's Liberation Army, No. 2 Huaxia West Road, Jianxi District, Luoyang 471031, Henan, China
| | - Yun Zhang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China; Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Road, Nanjing 211166, Jiangsu, China.
| | - Xiao-zhao Deng
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
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Yue M, Feng L, Tang SD, Wang JJ, Xue XX, Ding WL, Zhang Y, Deng XZ. Sex-specific association between X-linked Toll-like receptor 7 with the outcomes of hepatitis C virus infection. Gene 2014; 548:244-250. [PMID: 25034660 DOI: 10.1016/j.gene.2014.07.040] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 07/04/2014] [Accepted: 07/14/2014] [Indexed: 12/12/2022]
Abstract
Toll-like receptor 7 (TLR7) senses hepatitis C virus (HCV) infection and drives the host specific innate and adaptive immune response. The aim of this study was to estimate the distributions of TLR7 single nucleotide polymorphisms (SNPs), including rs179019 and rs3853839, as well as the effect of TLR7 gene variants on TLR7 mRNA expression and cytokine production in response to TLR7 agonist in vitro. TLR7 SNP genotyping was performed among a Chinese sample population of 418 patients with persistent HCV infection, 317 patients with HCV spontaneous clearance, and 989 healthy controls. TLR7 mRNA expression and TLR7-specific IFN-α and IL-6 secretion in peripheral blood mononuclear cells, derived from 60 healthy individuals in vitro, were then quantified. We identified the association of TLR7 rs3853839C allele, haplotype CC and haplotype AC (rs179019/rs3853839) with protection against HCV persistence in Chinese females (OR=0.49, 95% CI=0.29-0.81, P=0.01 for rs3853839 GC; OR=0.29, 95% CI=0.11-0.75, P=0.01 for rs3853839 CC; OR=0.51, 95% CI=0.38-0.77, P<0.01 for haplotype CC; OR=0.29, 95% CI=0.10-0.88, P=0.03 for haplotype AC). In addition, the rs3853839 CC genotype among female carriers had significantly low TLR7 mRNA expression (P=0.006 for GG vs. CC, P=0.021 for GC vs. CC), along with decreased IFN-α (P=0.002 for GG vs. CC, P=0.021 for GC vs. CC) and increased antiviral IL-6 production (P=0.002 for GG vs. CC, P=0.030 for GC vs. CC), after treatment with Imiquimod in vitro. The cytokine profile among rs3853839 CC genotype female carriers may indicate a pronounced protective effect against persistent HCV infection. The functional polymorphism of TLR7 rs3853839C allele was found to be sex-specific and associated with protection against HCV persistence among Chinese females, which may be due to specific IFN-α and IL-6 secretion profiles.
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Affiliation(s)
- Ming Yue
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China; School of Life Science and Technology, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China
| | - Le Feng
- Department of Infection and Immunity, Yixing People's Hospital, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, China
| | - Shai-di Tang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Jia-jia Wang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Xing-xin Xue
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China
| | - Wei-liang Ding
- Department of Clinical Laboratory, Yixing People's Hospital, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, China
| | - Yun Zhang
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
| | - Xiao-zhao Deng
- Huadong Research Institute for Medicine and Biotechnics, No. 293 Zhongshan East Road, Nanjing 210002, Jiangsu, China.
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Kushekhar K, van den Berg A, Nolte I, Hepkema B, Visser L, Diepstra A. Genetic associations in classical hodgkin lymphoma: a systematic review and insights into susceptibility mechanisms. Cancer Epidemiol Biomarkers Prev 2014; 23:2737-47. [PMID: 25205514 DOI: 10.1158/1055-9965.epi-14-0683] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Both targeted and genome-wide studies have revealed genetic associations for susceptibility, prognosis, and treatment-induced secondary malignancies and toxicities in classical Hodgkin lymphoma (cHL). This review gives a systematic and comprehensive overview of significant associations and places them into a biologic context. The strongest susceptibility polymorphisms have been found for the human leukocyte antigen (HLA) genes. These associations are specific for cHL overall or for subgroups based on tumor cell Epstein-Barr virus (EBV) status. These findings strongly suggest that EBV-specific immune responses influence cHL susceptibility in EBV(+) cHL and that immune responses targeting other tumor-associated antigens are important in EBV(-) cHL. Accordingly, most of the numerous other susceptibility loci map to genes that affect functionality of the immune system, underscoring the crucial role of the immune system in cHL development. The number of association studies on cHL prognosis is limited with one consistent association for the drug-metabolizing UGT1A1 gene. PRDM1 is associated with radiation-induced secondary malignancies and a small number of genes are associated with treatment-related toxicities. In conclusion, most loci showing genetic associations in cHL harbor genes with a potential functional relevance for cHL susceptibility.
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Affiliation(s)
- Kushi Kushekhar
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Ilja Nolte
- Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Bouke Hepkema
- Department of Laboratory Medicine, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
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Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy. Antiviral Res 2014. [DOI: 10.1128/9781555815493.ch19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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35
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Relevance of single-nucleotide polymorphisms in human TLR genes to infectious and inflammatory diseases and cancer. Genes Immun 2014; 15:199-209. [DOI: 10.1038/gene.2014.10] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 01/30/2014] [Accepted: 02/03/2014] [Indexed: 02/07/2023]
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36
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Wei XS, Wei CD, Tong YQ, Zhu CL, Zhang PA. Single nucleotide polymorphisms of toll-like receptor 7 and toll-like receptor 9 in hepatitis C virus infection patients from central China. Yonsei Med J 2014; 55:428-34. [PMID: 24532514 PMCID: PMC3936647 DOI: 10.3349/ymj.2014.55.2.428] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE To analyze the correlation of polymorphisms of toll-like receptor 7 (TLR7) (rs179009) and toll-like receptor 9 (TLR9) (rs187084) in hepatitis C virus (HCV) infections in the Han population. MATERIALS AND METHODS The genotypes of TLR7IVS2-151 in HCV infection were detected by Sanger sequencing using polymerase chain reaction-restriction fragment length polymorphism to determine the TLR9 T-1486C single nucleotide polymorphisms (SNP) for all enrolled patients. RESULTS We found no significant difference between males with spontaneous clearance of HCV versus those chronically infected [χ²=2.71, p=0.10, odd ratios (OR)=0.58, 95% confidence interval (CI) 0.31-1.11]. However, significant differences were found for the distribution of TLR7 (rs179009) in females (χ²=9.46, p=0.01). In females, a significant difference was also found between chronic hepatitis C and those with spontaneous clearance of HCV in terms of TLR7 IVS2-151G/A allele frequencies (χ²=9.50, p=0.00, OR=0.46, 95% CI 0.28-0.75). In HCV-infected patients, no significant association was found between the frequency of TLR9 genotypes and alleles. CONCLUSION The site of TLR7 IVS2-151 (rs179009) G/A may be a factor for susceptibility of chronic HCV in the female Han population. TLR9T-1486C (rs18084) SNP may not play a major role in HCV infection. However, individual risk profiles for HCV infection did vary by sex and this relationship should be further investigated.
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Affiliation(s)
- Xin-su Wei
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
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37
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Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that play an important role in host defence by recognizing pathogen-associated molecular patterns (PAMP). Recent studies indicate that TLR signalling plays an important role in progression of chronic liver diseases. Ongoing clinical trials suggest that therapeutic manipulation of TLR pathways may offer novel means of reversing chronic liver diseases. Upon activation by their respective ligands, TLRs initiate an intracellular pro-inflammatory/anti-inflammatory signalling cascade via recruitment of various adaptor proteins. TLR associated signalling pathways are tightly regulated to keep a check on inappropriate production of pro-inflammatory cytokines and interferons thereby preventing various autoimmune and inflammatory processes. Herein, we review the current state of knowledge of hepatic distribution, signalling pathways and therapeutic modulation of TLRs in chronic liver diseases.
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Affiliation(s)
- Vivek Kesar
- Department of Medicine, Recanati/Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Lenox Hill Hospital, New York, NY, USA
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38
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Abstract
The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.
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Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics 2013; 13:633-45. [PMID: 23730203 PMCID: PMC3492803 DOI: 10.2174/138920212803759712] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Revised: 10/08/2012] [Accepted: 10/08/2012] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.
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Affiliation(s)
- Yi-Tzu Lin
- Department of Medicine, Duke University Medical Center & Mandel Center for Hypertension and Atherosclerosis Research, Durham, NC 27710, USA
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40
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Medvedev AE. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J Interferon Cytokine Res 2013; 33:467-84. [PMID: 23675778 DOI: 10.1089/jir.2012.0140] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research.
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Affiliation(s)
- Andrei E Medvedev
- Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
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41
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Howell J, Angus P, Gow P, Visvanathan K. Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment. J Gastroenterol Hepatol 2013; 28:766-76. [PMID: 23432473 DOI: 10.1111/jgh.12170] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2013] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a significant global health problem, affecting over 150 million people worldwide. While the critical role of the adaptive immune system in HCV infection is well-established, the importance of the innate immune system in HCV infection has only been recognized in more recent years. Toll-like receptors form the cornerstone of the innate immune response, and there is considerable evidence for their crucial role in hepatitis C infection. This review outlines recent advances made in our understanding of the role of Toll-like receptor function in HCV infection, exploring how HCV manipulates host immunity to evade immune clearance and establish persistent infection despite leading to inflammatory hepatic damage.
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Affiliation(s)
- Jessica Howell
- Liver Transplant Unit, Austin Hospital, Victoria, Australia.
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Howell J, Sawhney R, Skinner N, Gow P, Angus P, Ratnam D, Visvanathan K. Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation. Am J Transplant 2013; 13:943-953. [PMID: 23425350 DOI: 10.1111/ajt.12165] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 12/27/2012] [Accepted: 12/30/2012] [Indexed: 01/25/2023]
Abstract
Recurrence of hepatitis C (HCV) postliver transplant is universal, with a subgroup developing rapid hepatic fibrosis. Toll-like receptors (TLRs) are critical to innate antiviral responses and HCV alters TLR function to evade immune clearance. Whether TLRs play a role in rapid HCV recurrence posttransplant is unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from 70 patients with HCV postliver transplant with TLR subclass-specific ligands and measured cytokine production, TLR expression and NK cell function. Rate of fibrosis progression was calculated using posttransplant liver biopsies graded by Metavir scoring (F0-4; R=fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4 units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid-fibrosers produced less IFNα with TLR7/8 stimulation (p=0.039), less IL-6 at baseline (p=0.027) and with TLR3 stimulation (p=0.008) and had lower TLR3-mediated monocyte IL-6 production (p=0.028) compared with HCV slow fibrosers. TLR7/8-mediated NKCD56 dim cell secretion of IFNγ was impaired in HCV rapid fibrosis (p=0.006) independently of IFNα secretion and TLR7/8 expression, while cytotoxicity remained preserved. Impaired TLR3 and TLR7/8-mediated cytokine responses may contribute to aggressive HCV recurrence postliver transplantation through impaired immune control of HCV and subsequent activation of fibrogenesis.
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Affiliation(s)
- J Howell
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia.,Department of Medicine, University of Melbourne, Australia
| | - R Sawhney
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia.,Department of Medicine, University of Melbourne, Australia
| | - N Skinner
- Innate Immune Laboratory, Monash University, Melbourne, Australia
| | - P Gow
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia.,Department of Medicine, University of Melbourne, Australia
| | - P Angus
- Liver Transplant Unit, Austin Hospital, Melbourne, Australia.,Department of Medicine, University of Melbourne, Australia
| | - D Ratnam
- Innate Immune Laboratory, Monash University, Melbourne, Australia
| | - K Visvanathan
- Innate Immune Laboratory, Monash University, Melbourne, Australia
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43
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Sehgal M, Khan ZK, Talal AH, Jain P. Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 2013; 4:1-25. [PMID: 25512691 PMCID: PMC4222345 DOI: 10.4137/vrt.s11046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew H Talal
- Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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Selective activation of Toll-like receptor 7 in activated hepatic stellate cells may modulate their profibrogenic phenotype. Biochem J 2012; 447:25-34. [PMID: 22765640 DOI: 10.1042/bj20112058] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Cholestatic liver injury may activate HSCs (hepatic stellate cells) to a profibrogenic phenotype, contributing to liver fibrogenesis. We have previously demonstrated the involvement of TLR (Toll-like receptor) 7 in the pathogenesis of biliary atresia. In the present study we investigated the ability of TLR7 to modulate the profibrogenic phenotype in HSCs. Obstructive jaundice was associated with significant down-regulation of TLR7. Primary HSCs isolated from BDL (bile duct ligation) rats with obstructive jaundice exhibited reduced expression of TLR7 and increased expression of α-SMA (α-smooth muscle actin) and collagen-α1 compared with sham rats, reflecting HSC-mediated changes. Treatment of primary activated rat HSCs and rat T6 cells with CL075, a TLR7 and TLR8 ligand, significantly decreased expression of MCP-1 (monocyte chemotactic protein-1), TGF-β1 (transforming growth factor-β1), collagen-α1 and MMP-2 (matrix metalloproteinase-2), and inhibited cell proliferation and migration. In contrast, silencing TLR7 expression with shRNA (short hairpin RNA) in T6 cells effectively blocked the effects of CL075 stimulation, reversing the changes in MCP-1, TGF-β1 and collagen-α1 expression and accelerating cell migration. Our results indicate that obstructive jaundice is associated with down-regulation of TLR7 and up-regulation of profibrogenic gene expression in HSCs. Selective activation of TLR7 may modulate the profibrogenic phenotype in activated HSCs associated with cholestatic liver injury.
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Lương KVQ, Nguyễn LTH. Theoretical basis of a beneficial role for vitamin D in viral hepatitis. World J Gastroenterol 2012; 18:5338-50. [PMID: 23082050 PMCID: PMC3471102 DOI: 10.3748/wjg.v18.i38.5338] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Revised: 03/22/2012] [Accepted: 05/06/2012] [Indexed: 02/06/2023] Open
Abstract
Abnormal bone metabolism and dysfunction of the calcium-parathyroid hormone-vitamin D axis have been reported in patients with viral hepatitis. Some studies suggested a relationship between vitamin D and viral hepatitis. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to the pathology of viral hepatitis (i.e., the major histocompatibility complex class II molecules, the vitamin D receptor, cytochrome P450, the renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, and the proteins regulated by the Sp1 promoter gene). Vitamin D also exerts its effects on viral hepatitis via non-genomic factors, i.e., matrix metalloproteinase, endothelial vascular growth factor, prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D could have a beneficial role in viral hepatitis. Calcitriol is best used for viral hepatitis because it is the active form of the vitamin D3 metabolite.
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Yang L, Seki E. Toll-like receptors in liver fibrosis: cellular crosstalk and mechanisms. Front Physiol 2012; 3:138. [PMID: 22661952 PMCID: PMC3357552 DOI: 10.3389/fphys.2012.00138] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Accepted: 04/24/2012] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that distinguish conserved microbial products, also known as pathogen-associated molecular patterns (PAMPs), from host molecules. Liver is the first filter organ between the gastrointestinal tracts and the rest of the body through portal circulation. Thus, the liver is a major organ that must deal with PAMPs and microorganisms translocated from the intestine and to respond to the damage associated molecular patterns (DAMPs) released from injured organs. These PAMPs and DAMPs preferentially activate TLR signaling on various cell types in the liver inducing the production of inflammatory and fibrogenic cytokines that initiate and prolong liver inflammation, thereby leading to fibrosis. We summarize recent findings on the role of TLRs, ligands, and intracellular signaling in the pathophysiology of liver fibrosis due to different etiology, as well as to highlight the potential role of TLR signaling in liver fibrosis associated with hepatitis C infection, non-alcoholic and alcoholic steatoheoatitis, primary biliary cirrhosis, and cystic fibrosis.
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Affiliation(s)
- Ling Yang
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine La Jolla, CA, USA
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47
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Zhang X, Kraft A, Broering R, Schlaak JF, Dittmer U, Lu M. Preclinical development of TLR ligands as drugs for the treatment of chronic viral infections. Expert Opin Drug Discov 2012; 7:597-611. [PMID: 22607384 DOI: 10.1517/17460441.2012.689281] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Toll-like receptors (TLRs) have been identified as key regulators of innate and adaptive immune responses in viral infection. Recent progress in this field revealed that there are significant interactions between the TLR system and pathogens in chronic viral infections. Therefore, TLR ligands have great potential for the treatment of chronic viral infections. AREAS COVERED This review provides an overview of the methodology for preclinical testing of TLR ligands for three major viral infections: hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). TLR ligands have shown potent antiviral activity in different cell culture systems as well as animal models for these infections and induce the production of antiviral cytokines, modulated cellular immunological functions and antiviral effects in vivo. EXPERT OPINION The recent progress in this field demonstrated that activation of a large number of TLR ligands is effective against viral infections in cell culture systems and animal models. Exploring these models, further in-depth elucidation of the molecular and immunological mechanisms of the antiviral activity of TLR ligands will be necessary to develop them into clinical useful drugs.
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Affiliation(s)
- Xiaoyong Zhang
- University of Duisburg-Essen, Institute of Virology, University Hospital of Essen, Essen, Germany.
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48
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Iwata R, Stieger B, Mertens JC, Müller T, Baur K, Frei P, Braun J, Vergopoulos A, Martin IV, Schmitt J, Goetze O, Bibert S, Bochud PY, Müllhaupt B, Berg T, Geier A. The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C. J Viral Hepat 2011; 18:768-78. [PMID: 20723035 DOI: 10.1111/j.1365-2893.2010.01363.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 μm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 μm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.
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Affiliation(s)
- R Iwata
- Clinic for Gastroenterology & Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich, Switzerland
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Sawhney R, Visvanathan K. Polymorphisms of toll-like receptors and their pathways in viral hepatitis. Antivir Ther 2011; 16:443-58. [PMID: 21685532 DOI: 10.3851/imp1820] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) are an important part of the innate immune response to a variety of pathogens including hepatic viral infections. Activation of TLRs stimulates a complex intracellular signalling cascade that results in production of proinflammatory cytokines and interferons important for antiviral responses as well as induction of the adaptive arm of the immune system. There is substantial evidence for an important role for TLRs and TLR-mediated signalling in the pathogenesis and outcomes of hepatitis B and C in particular, but it might also influence responses to other viral hepatitis infections. Several single nucleotide polymorphisms (SNPs) of TLRs, relevant adaptor molecules and cytokines mediated by TLR signalling have been described that alter innate immune responses and have been implicated in a variety of human diseases including viral and other infections. There is now significant evidence that a number of TLR SNPs can affect various clinical outcomes in Caucasian patients with chronic HCV. However, the role of these polymorphisms in acute and other chronic hepatitis infections, including HBV as well as in non-Caucasian populations, has not been elucidated. In addition, results for SNPs downstream of TLR activation, such as in relevant cytokines, are inconsistent and their influence requires further investigation to determine the clinical significance of genetic variations in these mediators.
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Affiliation(s)
- Rohit Sawhney
- Innate Immunity Laboratory, Department of Medicine, Monash University, Melbourne, Australia
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50
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TLR7 and TLR8 gene variations and susceptibility to hepatitis C virus infection. PLoS One 2011; 6:e26235. [PMID: 22022576 PMCID: PMC3192790 DOI: 10.1371/journal.pone.0026235] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2011] [Accepted: 09/22/2011] [Indexed: 01/29/2023] Open
Abstract
Toll-like receptors (TLRs) play pivotal roles in the innate immune system and control inflammatory responses and adaptive immunity. We previously evaluated associations between TLR7 and TLR8 gene SNPs and susceptibility to hepatitis C virus (HCV) infection. Our results suggested that TLR7IVS2-151G and TLR8-129G alleles were present at higher frequency in males of an HCV-infected group as compared to a control group (24.1% vs. 14.4%, p = 0.028; 17.6% vs. 6.8%, p = 0.004, respectively). Based upon their recognition of single stranded viral RNA, this suggested that TLR7 and TLR8 played a significant role in anti-HCV immune responses. Here, we studied the functional effects of these polymorphisms by analyzing the mRNA expressions of TLR7 and TLR8 and cytokine production induced ex vivo by TLR7- and TLR8-specific agonists using whole blood of subjects with different genotypes. The percentage of CD14+ cells from those with an AG haplotype that expressed TLR7 and TLR8 was significantly lower, but higher in intensity compared to cells from those with GG and AC haplotypes. Cells from those with an AG haplotype produced more IFN-α and less amounts of pro-inflammatory cytokines upon stimulation. This suggests that variations in TLR7 and TLR8 genes might impair immune responses during HCV infection.
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