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Colasanti O, Yu H, Lohmann V, Shin EC. Redefining the immune landscape of hepatitis A virus infection. Exp Mol Med 2025:10.1038/s12276-025-01431-2. [PMID: 40175697 DOI: 10.1038/s12276-025-01431-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/07/2025] [Accepted: 01/17/2025] [Indexed: 04/04/2025] Open
Abstract
Despite the development of effective vaccines against hepatitis A virus (HAV) infection, outbreaks of acute hepatitis A still occur globally, such that HAV remains a major cause of acute viral hepatitis. Most patients with acute hepatitis A recover spontaneously; however, some adult cases result in acute liver failure due to immune-mediated liver damage. Previous studies suggested that HAV evades the innate immune response through strong counteractive mechanisms, and that HAV-specific CD8+ T cells contribute to liver damage in patients with acute hepatitis A. However, recent research findings have led to revisions of old hypotheses. Here we will describe the most current knowledge regarding the innate immune response to HAV and the HAV-mediated counteractions against innate immune responses. Additionally, we will discuss the roles of various types of T cells in viral clearance and liver injury in patients with acute hepatitis A.
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Affiliation(s)
- Ombretta Colasanti
- Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, Center for Integrative Infectious Disease Research, Heidelberg, Germany
| | - Hosun Yu
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Volker Lohmann
- Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, Center for Integrative Infectious Disease Research, Heidelberg, Germany.
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science, Daejeon, Republic of Korea.
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Abbasi A, Costafreda MI, Ballesteros A, Jacques J, Tami C, Manangeeswaran M, Casasnovas JM, Kaplan G. Molecular Basis for the Differential Function of HAVCR1 Mucin Variants. Biomedicines 2024; 12:2643. [PMID: 39595207 PMCID: PMC11592376 DOI: 10.3390/biomedicines12112643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/07/2024] [Accepted: 11/09/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: The hepatitis A virus (HAV) cellular receptor 1 (HAVCR1) is a type I integral membrane glycoprotein discovered in monkeys and humans as a HAV receptor. HAVCR1 contains an N-terminal immunoglobulin-like variable domain (IgV) followed by a mucin-like domain (Muc), a transmembrane domain, and a cytoplasmic tail with a canonical tyrosine kinase phosphorylation site. The IgV binds phosphatidylserine on apoptotic cells, extracellular vesicles, and enveloped viruses. Insertions/deletions at position 156 (156ins/del) of the Muc were associated in humans with susceptibility to atopic, autoimmune, and infectious diseases. However, the molecular basis for the differential function of the HAVCR1 variants is not understood. Methods: We used mutagenesis, apoptotic cell binding, and signal transduction analyses to study the role of the 156ins/del in the function of HAVCR1. Results: We found that the HAVCR1 variant without insertions at position 156 (156delPMTTTV, or short-HAVCR1) bound more apoptotic cells than that containing a six amino acid insertion (156insPMTTTV, or long-HAVCR1). Furthermore, short-HAVCR1 induced stronger cell signaling and phagocytosis than long-HAVCR1. Conclusions: Our data indicated that the 156ins/del determine how the IgV is presented at the cell surface and modulate HAVCR1 binding, signaling, and phagocytosis, suggesting that variant-specific targeting could be used as therapeutic interventions to treat immune and infectious diseases.
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Affiliation(s)
- Abdolrahim Abbasi
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - Maria Isabel Costafreda
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - Angela Ballesteros
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - Jerome Jacques
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - Cecilia Tami
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - Mohanraj Manangeeswaran
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
| | - José M. Casasnovas
- Department of Macromolecular Structures, Centro Nacional de Biotecnología and Consejo Superior de Investigaciones Científicas (CNB-CSIC), Campus Cantoblanco, 28049 Madrid, Spain;
| | - Gerardo Kaplan
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; (A.A.); (A.B.); (J.J.); (C.T.); (M.M.)
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Tutunea-Fatan E, Arumugarajah S, Suri RS, Edgar CR, Hon I, Dikeakos JD, Gunaratnam L. Sensing Dying Cells in Health and Disease: The Importance of Kidney Injury Molecule-1. J Am Soc Nephrol 2024; 35:795-808. [PMID: 38353655 PMCID: PMC11164124 DOI: 10.1681/asn.0000000000000334] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024] Open
Abstract
Kidney injury molecule-1 (KIM-1), also known as T-cell Ig and mucin domain-1 (TIM-1), is a widely recognized biomarker for AKI, but its biological function is less appreciated. KIM-1/TIM-1 belongs to the T-cell Ig and mucin domain family of conserved transmembrane proteins, which bear the characteristic six-cysteine Ig-like variable domain. The latter enables binding of KIM-1/TIM-1 to its natural ligand, phosphatidylserine, expressed on the surface of apoptotic cells and necrotic cells. KIM-1/TIM-1 is expressed in a variety of tissues and plays fundamental roles in regulating sterile inflammation and adaptive immune responses. In the kidney, KIM-1 is upregulated on injured renal proximal tubule cells, which transforms them into phagocytes for clearance of dying cells and helps to dampen sterile inflammation. TIM-1, expressed in T cells, B cells, and natural killer T cells, is essential for cell activation and immune regulatory functions in the host. Functional polymorphisms in the gene for KIM-1/TIM-1, HAVCR1 , have been associated with susceptibility to immunoinflammatory conditions and hepatitis A virus-induced liver failure, which is thought to be due to a differential ability of KIM-1/TIM-1 variants to bind phosphatidylserine. This review will summarize the role of KIM-1/TIM-1 in health and disease and its potential clinical applications as a biomarker and therapeutic target in humans.
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Affiliation(s)
- Elena Tutunea-Fatan
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
| | - Shabitha Arumugarajah
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Rita S. Suri
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Cassandra R. Edgar
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Ingrid Hon
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jimmy D. Dikeakos
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Lakshman Gunaratnam
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Quinchia J, Blázquez-García M, Torrente-Rodríguez RM, Ruiz-Valdepeñas Montiel V, Serafín V, Rejas-González R, Montero-Calle A, Orozco J, Pingarrón JM, Barderas R, Campuzano S. Disposable electrochemical immunoplatform to shed light on the role of the multifunctional glycoprotein TIM-1 in cancer cells invasion. Talanta 2024; 267:125155. [PMID: 37696234 DOI: 10.1016/j.talanta.2023.125155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/24/2023] [Accepted: 09/02/2023] [Indexed: 09/13/2023]
Abstract
Detecting overexpression of cancer biomarkers is an excellent tool for diagnostic/prognostic and follow-up of patients with cancer or their response to treatment. This work illustrates the relevance of interrogating the levels of T-cell immunoglobulin and mucin domain 1 (TIM-1) protein as a diagnostic/prognostic biomarker of high-prevalence breast and lung cancers by using an amperometric disposable magnetic microparticles-assisted immunoplatform. The developed method integrates the inherent advantages of carboxylic acid-functionalized magnetic beads (HOOC-MBs) as pre-concentrator support and the amperometric transduction at screen-printed carbon electrodes (SPCEs). The immunoplatform involves a sandwich-type immunoassay assembled on HOOC-MBs through the specific capture/labeling of TIM-1 using capture antibodies and horseradish peroxidase (HRP)-conjugated biotinylated detection antibodies as biorecognition elements. The magnetic immunoconjugates were confined onto the working electrode (WE) surface of the SPCEs for amperometric detection using the hydroquinone/hydrogen peroxide/HRP (HQ/H2O2/HRP) redox system. The method allows the selective detection of TIM-1 protein over the 87-7500 pg mL-1 concentration range in only 45 min, with a limit of detection of 26 pg mL-1. The developed bioplatform was successfully applied to the analysis of breast and lung cancer cell extracts, providing the first quantitative results of the target glycoprotein in these types of samples.
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Affiliation(s)
- Jennifer Quinchia
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain; Max Planck Tandem Group in Nanobioengineering, Institute of Chemistry, Faculty of Natural and Exact Sciences, University of Antioquia. Complejo Ruta N, Calle 67 No. 52-20, Medellín, 050010, Colombia
| | - Marina Blázquez-García
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Rebeca M Torrente-Rodríguez
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Víctor Ruiz-Valdepeñas Montiel
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Verónica Serafín
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | | | - Ana Montero-Calle
- UFIEC, Instituto de Salud Carlos III, 28220, Majadahonda, Madrid, Spain
| | - Jahir Orozco
- Max Planck Tandem Group in Nanobioengineering, Institute of Chemistry, Faculty of Natural and Exact Sciences, University of Antioquia. Complejo Ruta N, Calle 67 No. 52-20, Medellín, 050010, Colombia
| | - José M Pingarrón
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain
| | - Rodrigo Barderas
- UFIEC, Instituto de Salud Carlos III, 28220, Majadahonda, Madrid, Spain.
| | - Susana Campuzano
- Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Pza. de Las Ciencias 2, 28040, Madrid, Spain.
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Kanda T, Sasaki-Tanaka R, Ishii K, Suzuki R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Li TC, Kunita S, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis A virus research and clinical practice guidelines for hepatitis A virus infection in Japan. Hepatol Res 2024; 54:4-23. [PMID: 37906585 DOI: 10.1111/hepr.13983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/06/2023] [Accepted: 10/23/2023] [Indexed: 11/02/2023]
Abstract
In 2018, there was a hepatitis A outbreak in Japan, and hepatitis A virus (HAV) infection is considered a sexually transmitted disease. In general, patients with hepatitis A should be given attention, and this disease should be prevented more than ever. The Japan Agency for Medical Research and Development (AMED) Hepatitis A and E viruses (HAV and HEV) Study Group has worked on the project to create "Recent Advances in Hepatitis A Virus (HAV) Research and Clinical Practice Guidelines for HAV Infection in Japan". The group consists of expert hepatologists and virologists who gathered at virtual meeting on August 5, 2023. Data about the pathogenesis, infection routes, diagnosis, complications, several factors for the severities, vaccination, and current and future treatments for hepatitis A were discussed and debated for a draft version. The participants assessed the quality of cited studies. The finalized recommendations are presented in this review. The recent advances in HAV research and clinical practice for HAV infection in Japan, have been reviewed by the AMED HAV and HEV Study Group.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Yufu, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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Van Damme P, Pintó RM, Feng Z, Cui F, Gentile A, Shouval D. Hepatitis A virus infection. Nat Rev Dis Primers 2023; 9:51. [PMID: 37770459 DOI: 10.1038/s41572-023-00461-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 09/30/2023]
Abstract
Hepatitis A is a vaccine-preventable infection caused by the hepatitis A virus (HAV). Over 150 million new infections of hepatitis A occur annually. HAV causes an acute inflammatory reaction in the liver that usually resolves spontaneously without chronic sequelae. However, up to 20% of patients experience a prolonged or relapsed course and <1% experience acute liver failure. Host factors, such as immunological status, age, pregnancy and underlying hepatic diseases, can affect the severity of disease. Anti-HAV IgG antibodies produced in response to HAV infection persist for life and protect against re-infection; vaccine-induced antibodies against hepatitis A confer long-term protection. The WHO recommends vaccination for individuals at higher risk of infection and/or severe disease in countries with very low and low hepatitis A virus endemicity, and universal childhood vaccination in intermediate endemicity countries. To date, >25 countries worldwide have implemented such programmes, resulting in a reduction in the incidence of HAV infection. Improving hygiene and sanitation, rapid identification of outbreaks and fast and accurate intervention in outbreak control are essential to reducing HAV transmission.
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Affiliation(s)
- Pierre Van Damme
- Centre for the Evaluation of Vaccination, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
| | - Rosa M Pintó
- Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Zongdi Feng
- Centre for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Fuqiang Cui
- Department of Laboratorial Science and Technology & Vaccine Research Center, School of Public Health, Peking University, Beijing, People's Republic of China
| | - Angela Gentile
- Department of Epidemiology, Hospital de Niños Ricardo Gutierrez, University of Buenos Aires, Buenos Aires, Argentina
| | - Daniel Shouval
- Institute of Hepatology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
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Gabrielli F, Alberti F, Russo C, Cursaro C, Seferi H, Margotti M, Andreone P. Treatment Options for Hepatitis A and E: A Non-Systematic Review. Viruses 2023; 15:1080. [PMID: 37243166 PMCID: PMC10221699 DOI: 10.3390/v15051080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.
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Affiliation(s)
- Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Francesco Alberti
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Cristina Russo
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Hajrie Seferi
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Marzia Margotti
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Hattori T, Saito T, Miyamoto H, Kajihara M, Igarashi M, Takada A. Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells. Viruses 2022; 14:v14102124. [PMID: 36298679 PMCID: PMC9611583 DOI: 10.3390/v14102124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/18/2022] [Accepted: 09/21/2022] [Indexed: 11/29/2022] Open
Abstract
Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.
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Affiliation(s)
- Takanari Hattori
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Takeshi Saito
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Masahiro Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Manabu Igarashi
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
- One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan
- Correspondence: ; Tel.: +81-11-706-9502; Fax: +81-11-706-7310
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9
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Jiao W, Xie S, Liang Z, Pan J, Yang X, Tong H, Zhao Y, Cao R. P34L Mutation of swine TIM-1 enhances its ability to mediate Japanese encephalitis virus infection. Vet Microbiol 2022; 274:109555. [PMID: 36095877 DOI: 10.1016/j.vetmic.2022.109555] [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: 03/08/2022] [Revised: 08/18/2022] [Accepted: 09/01/2022] [Indexed: 10/31/2022]
Abstract
Japanese encephalitis virus (JEV) is a major causative agent of neurological infection affecting humans and pigs. Human T Cell Immunoglobulin and Mucin Domain 1 (hTIM-1) enhances the infection of JEV through virion-associated phosphatidylserine (PS) binding. Here, five swine TIM-1 (sTIM-1) gene variants were cloned from pig lung tissues by reverse-transcriptase polymerase chain reaction (RT-PCR). Sequence alignment analysis revealed that the gene homology between the sTIM-1 and hTIM-1 was 42.3-43.8%. Furthermore, ectopic expression of all five sTIM-1 variants in 293 T cells can promote JEV entry and infection. However, sTIM-1 V3 exhibited significantly less potent at promoting virus entry compared to the other four variants. Further studies revealed that the 34th amino acid of sTIM-1is critical for the entry of JEV, which is Pro34 in sTIM-1V3 while Leu34 in other four sTIM-1 variants. Mechanically, leucine at locus 34 was associated with the membrane distribution of sTIM-1, thereby affecting viral entry and infection. In total, our findings provide evidence that the PS receptor sTIM-1 promotes the infection of JEV and that the 34th amino acid position is critical for sTIM-1 to mediate viral infection.
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Affiliation(s)
- Wenlong Jiao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Shengda Xie
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Zhenjie Liang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Junhui Pan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xingmiao Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - He Tong
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yundi Zhao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Ruibing Cao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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10
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Zhang M, Wang X, Hu L, Zhang Y, Zheng H, Wu H, Wang J, Luo L, Xiao H, Qiao C, Li X, Huang W, Wang Y, Feng J, Chen G. TIM-1 Augments Cellular Entry of Ebola Virus Species and Mutants, Which Is Blocked by Recombinant TIM-1 Protein. Microbiol Spectr 2022; 10:e0221221. [PMID: 35384693 PMCID: PMC9241846 DOI: 10.1128/spectrum.02212-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/07/2022] [Indexed: 01/12/2023] Open
Abstract
Ebola virus, a member of the Filoviridae family, utilizes the attachment factors on host cells to support its entry and cause severe tissue damage. TIM-1 has been identified as a predominant attachment factor via interaction with phosphatidylserine (PS) localized on the viral envelope and glycoprotein (GP). In this study, we give the first demonstration that TIM-1 enhances the cellular entry of three species of Ebola virus, as well as those harboring GP mutations (A82V, T544I, and A82V T544I). Furthermore, two TIM-1 variants (i.e., TIM-1-359aa and TIM-1-364aa) had comparable effects on promoting Zaire Ebola virus (EBOV) attachment, internalization, and infection. Importantly, recombinant TIM-1 ectodomain (ECD) protein could decrease the infectivity of Ebola virus and display synergistic inhibitory effects with ADI-15946, a monoclonal antibody with broad neutralizing activity to Ebola virus. Of note, EBOV strains harboring GP mutations (K510E and D552N), which were refractory to antibody treatment, were still sensitive to TIM-1 protein-mediated impairment of infectivity, indicating that TIM-1 protein may represent an alternative therapeutic regimen when antibody evasion occurs. IMPORTANCE The viral genome has acquired numerous mutations with the potential to increase transmission during the 2013-to-2016 outbreak of Ebola virus. EBOV strains harboring GP mutations (A82V, T544I, and A82V T544I), which have been identified to increase viral infectivity in humans, have attracted our attention. Herein, we give the first report that polymorphic TIM-1 enhances the infectivity of three species of Ebola virus, as well as those harboring GP mutations (A82V, T544I, and A82V T544I). We show that recombinant TIM-1 ECD protein could decrease the infectivity of Ebola virus with or without a point mutation and displays synergistic inhibitory effects with ADI-15946. Furthermore, TIM-1 protein potently blocked cell entry of antibody-evading Ebola virus species. These findings highlight the role of TIM-1 in Ebola virus infection and indicate that TIM-1 protein represents a potential therapeutic avenue for Ebola virus and its mutated species.
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Affiliation(s)
- Min Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Xinwei Wang
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China
| | - Linhan Hu
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China
| | - Yuting Zhang
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China
| | - Hang Zheng
- Inner Mongolia Key Lab of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China
| | - Haiyan Wu
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Jing Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Longlong Luo
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - He Xiao
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Chunxia Qiao
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Xinying Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Weijin Huang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Jiannan Feng
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Guojiang Chen
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
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11
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Karmakova ТА, Sergeeva NS, Kanukoev КY, Alekseev BY, Kaprin АD. Kidney Injury Molecule 1 (KIM-1): a Multifunctional Glycoprotein and Biological Marker (Review). Sovrem Tekhnologii Med 2021; 13:64-78. [PMID: 34603757 PMCID: PMC8482821 DOI: 10.17691/stm2021.13.3.08] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
KIM-1 (kidney injury molecule 1) is a transmembrane glycoprotein also known as HAVcr-1 and TIM-1 belongs to the T-cell immunoglobulin and mucin domain family (TIM) of proteins. TIM glycoproteins are presented on the immune cells and participate in the regulation of immune reactions. KIM-1 differs from other members of its family in that it is expressed not only by immunocompetent cells but epithelial cells as well. Cellular and humoral effects mediated by KIM-1 are involved in a variety of physiological and pathophysiological processes. Current understanding of the mechanisms determining the participation of KIM-1 in viral invasion, the immune response regulation, adaptive reactions of the kidney epithelium to acute ischemic or toxic injury, in progression of chronic renal diseases, and kidney cancer development have been presented in this review. Data of clinical researches demonstrating the association of KIM-1 with viral diseases and immune disorders have also been analyzed. Potential application of KIM-1 as urinary or serological marker in renal and cardiovascular diseases has been considered.
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Affiliation(s)
- Т А Karmakova
- Leading Researcher, Department of Predicting the Effectiveness of Conservative Therapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia
| | - N S Sergeeva
- Professor, Head of the Department of Predicting the Effectiveness of Conservative Therapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia; Professor, Department of Biology; Pirogov Russian National Research Medical University, 1 Ostrovitianova St., Moscow, 117997, Russia
| | - К Yu Kanukoev
- Urologist, Department of Urology with Chemotherapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia
| | - B Ya Alekseev
- Professor, Deputy General Director for Science; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 4 Koroleva St., Obninsk, 249036, Russia
| | - А D Kaprin
- Professor, Academician of the Russian Academy of Sciences, General Director; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 4 Koroleva St., Obninsk, 249036, Russia
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12
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Wang M, Feng Z. Mechanisms of Hepatocellular Injury in Hepatitis A. Viruses 2021; 13:v13050861. [PMID: 34066709 PMCID: PMC8151331 DOI: 10.3390/v13050861] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.
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Affiliation(s)
- Minghang Wang
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - Zongdi Feng
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Correspondence:
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13
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Medrzycki M, Kamili S, Purdy MA. Hepatitis A virus survival on drug paraphernalia. J Viral Hepat 2020; 27:1484-1494. [PMID: 32810349 DOI: 10.1111/jvh.13379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 08/04/2020] [Accepted: 08/07/2020] [Indexed: 12/09/2022]
Abstract
The ongoing hepatitis A outbreaks in multiple states in the United States have concerned public health authorities since March 2017. The outbreaks have spread throughout 30 states and include primarily persons who use drugs, including persons who inject drugs (PWID) and persons experiencing homelessness. Contaminated drug injection paraphernalia and sharing of these items could potentially aid in transmission of hepatitis A virus (HAV) among these populations. We examined HAV survival on drug paraphernalia frequently shared among PWIDs. The effect of low pH on HAV survival using citric acid, which is frequently used by PWIDs during dose preparation, was investigated. We compared the plaque assay results with those concurrently obtained by qRT-PCR to establish whether HAV RNA levels could be used as surrogates for plaque assay results. HAV suspended in minimal essential media at room temperature infected FRhK4 cells for more than 17 weeks. HAV remained viable in syringes/needles for up to 10 weeks depending on the gauge of the needles and the syringe dead volumes, and on cookers, tourniquets and cotton balls/filter surfaces for up to 4 weeks. HAV retained its infectivity for more than 10 weeks at pH as low as 2. In conclusion, our findings show that HAV survives and remains infective in or on injection drug use equipment for 1 to 10 weeks depending on the type of paraphernalia examined and environmental conditions. These findings suggest that contaminated drug paraphernalia can potentially facilitate the transmission of HAV within populations who share these items.
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Affiliation(s)
- Magdalena Medrzycki
- Division of Viral Hepatitis, NCHHSTP, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Saleem Kamili
- Division of Viral Hepatitis, NCHHSTP, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Michael A Purdy
- Division of Viral Hepatitis, NCHHSTP, Centers for Disease Control and Prevention, Atlanta, GA, USA
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14
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Tim-4 functions as a scavenger receptor for phagocytosis of exogenous particles. Cell Death Dis 2020; 11:561. [PMID: 32703939 PMCID: PMC7378189 DOI: 10.1038/s41419-020-02773-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/17/2022]
Abstract
The phosphatidylserine (PS) receptor Tim-4 mediates phagocytosis of apoptotic cells by binding to PS exposed on the surface of these cells, and thus functions as a PS receptor for apoptotic cells. Some of PS receptors are capable of recognizing other molecules, such as LPS on bacteria, besides PS on apoptotic cells. However, it is unclear whether Tim-4 perceives other molecules like the PS receptors. Here, we report that Tim-4 facilitates the phagocytosis of exogenous particles as well as apoptotic cells. Similar to the process that occurs during Tim-4-mediated efferocytosis, the uptake of exogenous E. coli and S. aureus bioparticles was promoted by overexpression of Tim-4 on phagocytes, whereas phagocytosis of the bioparticles was reduced in Tim-4-deficient cells. A truncation mutant of Tim-4 lacking the cytoplasmic tail promoted phagocytosis of the particles, but a mutant lacking the IgV or the mucin domain failed to enhance phagocytosis. However, expression of Tim-4AAA (a mutant form of Tim-4 that does not bind phosphatidylserine and does not promote efferocytosis) still promoted phagocytosis. Tim-4-mediated phagocytosis was not blocked by expression of the phosphatidylserine-binding protein Anxa5. Furthermore, binding of lipopolysaccharide (LPS), which is found in the outer membrane of Gram-negative bacteria, was higher in Tim-4-overexpressing cells than in Tim-4-deficient cells. In summary, our study suggests that Tim-4 acts as a scavenger receptor and mediates phagocytosis of exogenous particles in a phosphatidylserine-independent manner.
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15
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Jouanguy E. Human genetic basis of fulminant viral hepatitis. Hum Genet 2020; 139:877-884. [PMID: 32285199 PMCID: PMC7153696 DOI: 10.1007/s00439-020-02166-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/04/2020] [Indexed: 12/27/2022]
Abstract
In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH, and this is the key issue to be addressed for this disease. In mice, mouse hepatitis virus 3 (MHV3) infection is the main model for dissecting FVH pathogenesis. Susceptibility to MHV3 differs between genetic backgrounds, with high and low mortality in C57BL6 and A/J mice, respectively. FVH pathogenesis in mice is related to uncontrolled inflammation and fibrinogen deposition. In humans, FVH is typically sporadic, but rare familial forms also exist, suggesting that there may be causal monogenic inborn errors. A recent study reported a single-gene inborn error of human immunity underlying FVH. A patient with autosomal recessive complete IL-18BP deficiency was shown to have FVH following HAV infection. The mechanism probably involves enhanced IL-18- and IFN-γ-dependent killing of hepatocytes by NK and CD8 T cytotoxic cells. Proof-of-principle that FVH can be genetic is important clinically, for the affected patients and their families, and immunologically, for the study of immunity to viruses in the liver. Moreover, the FVH-causing IL18BP genotype suggests that excessive IL-18 immunity may be a general mechanism underlying FVH, perhaps through the enhancement of IFN-γ immunity.
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Affiliation(s)
- Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-1163, Necker Hospital for Sick Children, Paris, France. .,Imagine Institute, Paris University, Paris, France. .,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
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16
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Liu Y, Xu HB. Genetic polymorphisms of rs9313422 G>C and rs41297579 G>A at the promoter of TIM-1 gene contribute to the risk of community-acquired pneumonia in children. J Clin Lab Anal 2019; 34:e23095. [PMID: 31800133 PMCID: PMC7083502 DOI: 10.1002/jcla.23095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/18/2019] [Accepted: 10/07/2019] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To investigate the association of genetic polymorphisms of rs9313422 G>C and rs41297579 G>A at the promoter of TIM-1 gene with the risk of community-acquired pneumonia (CAP) in children. METHODS A total of 112 children with CAP were included as the case group. Another 120 healthy children were enrolled as the control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied for the genotyping of rs9313422 G>C and rs41297579 G>A in the promoter region of TIM-1. RESULTS rs9313422 G>C was related to the risk of CAP in children under codominant model, dominant model, recessive model, and allele model. Besides, the A allele of rs41297579 G>A could increase the risk of CAP in children. Besides, the haplotype GA (rs9313422-rs41297579) and GG reduced the risk of children CAP, while haplotype CA had an elevated risk. rs9313422 G>C and rs41297579 G>A polymorphisms were both associated with the severity of CAP in children, and the rs9313422 G>C was also related to the ICU admission rate. In addition, patients carried with the mutant homozygotes of rs9313422 G>C and rs41297579 G>A showed higher levels of white blood cell (WBC), procalcitonin (PCT), and C-reactive protein (CRP) than the wild type and heterozygous genotypes carriers. CONCLUSION rs9313422 G>C and rs41297579 G>A polymorphisms in the promoter region of TIM-1 could increase the risk of CAP in children and showed a relation with inflammatory responses and severity.
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Affiliation(s)
- Yang Liu
- Department of Pediatrics, First Affiliated Hospital of Yangtze University, Jingzhou, China
| | - Hong-Bo Xu
- Neonatal Department, Maternal and Child Health Hospital of Jingzhou City, Jingzhou, China
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17
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Lai ACY, Chi PY, Thio CLP, Han YC, Kao HN, Hsieh HW, Gervay-Hague J, Chang YJ. α-Lactosylceramide Protects Against iNKT-Mediated Murine Airway Hyperreactivity and Liver Injury Through Competitive Inhibition of Cd1d Binding. Front Chem 2019; 7:811. [PMID: 31850305 PMCID: PMC6893574 DOI: 10.3389/fchem.2019.00811] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/11/2019] [Indexed: 11/23/2022] Open
Abstract
Invariant natural killer T (iNKT) cells, which are activated by T cell receptor (TCR)-dependent recognition of lipid-based antigens presented by the CD1d molecule, have been shown to participate in the pathogenesis of many diseases, including asthma and liver injury. Previous studies have shown the inhibition of iNKT cell activation using lipid antagonists can attenuate iNKT cell-induced disease pathogenesis. Hence, the development of iNKT cell-targeted glycolipids can facilitate the discovery of new therapeutics. In this study, we synthesized and evaluated α-lactosylceramide (α-LacCer), an α-galactosylceramide (α-GalCer) analog with lactose substitution for the galactose head and a shortened acyl chain in the ceramide tail, toward iNKT cell activation. We demonstrated that α-LacCer was a weak inducer for both mouse and human iNKT cell activation and cytokine production, and the iNKT induction by α-LacCer was CD1d-dependent. However, when co-administered with α-GalCer, α-LacCer inhibited α-GalCer-induced IL-4 and IFN-γ production from iNKT cells. Consequently, α-LacCer also ameliorated both α-GalCer and GSL-1-induced airway hyperreactivity and α-GalCer-induced neutrophilia when co-administered in vivo. Furthermore, we were able to inhibit the increases of ConA-induced AST, ALT and IFN-γ serum levels through α-LacCer pre-treatment, suggesting α-LacCer could protect against ConA-induced liver injury. Mechanistically, we discerned that α-LacCer suppressed α-GalCer-stimulated cytokine production through competing for CD1d binding. Since iNKT cells play a critical role in the development of AHR and liver injury, the inhibition of iNKT cell activation by α-LacCer present a possible new approach in treating iNKT cell-mediated diseases.
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Affiliation(s)
| | - Po-Yu Chi
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | | | - Yun-Chiann Han
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsien-Neng Kao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsiao-Wu Hsieh
- Department of Chemistry, University of California, Davis, Davis, CA, United States
| | | | - Ya-Jen Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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18
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Walker CM. Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a033472. [PMID: 29844218 DOI: 10.1101/cshperspect.a033472] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained. The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted.
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Affiliation(s)
- Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's, Columbus, Ohio 43004
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19
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Belkaya S, Michailidis E, Korol CB, Kabbani M, Cobat A, Bastard P, Lee YS, Hernandez N, Drutman S, de Jong YP, Vivier E, Bruneau J, Béziat V, Boisson B, Lorenzo-Diaz L, Boucherit S, Sebagh M, Jacquemin E, Emile JF, Abel L, Rice CM, Jouanguy E, Casanova JL. Inherited IL-18BP deficiency in human fulminant viral hepatitis. J Exp Med 2019; 216:1777-1790. [PMID: 31213488 PMCID: PMC6683989 DOI: 10.1084/jem.20190669] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 12/21/2022] Open
Abstract
Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.
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Affiliation(s)
- Serkan Belkaya
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | | | - Cecilia B Korol
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Mohammad Kabbani
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Paul Bastard
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Yoon Seung Lee
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Nicholas Hernandez
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Scott Drutman
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Ype P de Jong
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY.,Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - Eric Vivier
- Aix Marseille Université, INSERM, Centre National de la Recherche Scientifique, Centre d'Immunologie de Marseille-Luminy, Marseille, France.,Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.,Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
| | - Julie Bruneau
- Paris Descartes University, Imagine Institute, Paris, France.,Department of Pathology, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France
| | - Vivien Béziat
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Lazaro Lorenzo-Diaz
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Soraya Boucherit
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Mylène Sebagh
- Department of Pathology, Hepato-biliary Center, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Villejuif, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases, Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, University of Paris Sud-Saclay, Le Kremlin Bicêtre, France.,INSERM U1174, University of Paris Sud-Saclay, Hepatinov, Orsay, France
| | - Jean-François Emile
- Department of Pathology, Assistance Publique-Hôpitaux de Paris, Ambroise Paré Hospital, Boulogne-Billancourt, France
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY .,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France.,Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France.,Howard Hughes Medical Institute, New York, NY
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Song J, Yu J, Prayogo GW, Cao W, Wu Y, Jia Z, Zhang A. Understanding kidney injury molecule 1: a novel immune factor in kidney pathophysiology. Am J Transl Res 2019; 11:1219-1229. [PMID: 30972157 PMCID: PMC6456506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/02/2019] [Indexed: 06/09/2023]
Abstract
Kidney injury molecule 1 (KIM-1) is a type I membrane protein, comprising an extracellular portion and a cytoplasmic portion. It is also named as HAVCR1 (Hepatitis A virus cellular receptor 1) or TIM1 (T-cell immunoglobulin mucin receptor 1), and is expressed in the kidney, liver, and spleen. KIM-1 plays different roles via various molecular targets in immune diseases and kidney injury. KIM-1 is involved in HAV infections, autoimmunity, immune tolerance, and atopic diseases. The urinary KIM-1 level is closely related to its tissue level, and correspondingly related to kidney tissue damage. KIM-1 is not only an early biomarker of acute kidney injury (AKI), but also has a potential role in predicting the long-term renal outcome. In this review, we provide a summary of KIM-1's activities, focusing on the latest studies concerning the important roles of KIM-1 in the immune system and kidney diseases.
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Affiliation(s)
- Jiayu Song
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Jing Yu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Gabriella Wenda Prayogo
- Department of Endocrinology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
| | - Weidong Cao
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Yimei Wu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
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Niu J, Jiang Y, Xu H, Zhao C, Zhou G, Chen P, Cao R. TIM-1 Promotes Japanese Encephalitis Virus Entry and Infection. Viruses 2018; 10:E630. [PMID: 30441759 PMCID: PMC6265761 DOI: 10.3390/v10110630] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/09/2018] [Accepted: 11/10/2018] [Indexed: 01/23/2023] Open
Abstract
Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus, the leading cause of viral-induced encephalitis. Several host molecules have been identified as the JEV attachment factor; however, the molecules involved in JEV entry remain poorly understood. In the present study, we demonstrate that TIM-1 is important for efficient infection by JEV. Firstly, three TIM-1 variants (V1, V2, and V3) were cloned from A549 cells, and we revealed that only ectopically TIM-1 V2 expression in 293T cells significantly promotes JEV attachment, entry and infection. Point mutation of phosphatidylserine (Ptdser) binding pocket in the TIM-1 IgV domain dampened JEV entry, indicating that TIM-1-mediated JEV infection is Ptdser-dependent. Furthermore, we found the cytoplasmic domain of TIM-1 is also required for enhancing JEV entry. Additionally, knock down of TIM-1 expression in A549 cells impaired JEV entry and infection, but not attachment, suggesting that additional factors exist in A549 cells that allow the virus to bind. In conclusion, our findings demonstrate that TIM-1 promotes JEV infection as an entry cofactor, and the polymorphism of TIM-1 is associated with JEV susceptibility to host cells.
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Affiliation(s)
- Jichen Niu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Ya Jiang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Hao Xu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Changjing Zhao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Guodong Zhou
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Puyan Chen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Ruibing Cao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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Liu L, Song Z, Zhao Y, Li C, Wei H, Ma J, Du Y. HAVCR1 expression might be a novel prognostic factor for gastric cancer. PLoS One 2018; 13:e0206423. [PMID: 30388143 PMCID: PMC6214515 DOI: 10.1371/journal.pone.0206423] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 10/13/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis A virus cellular receptor 1 (HAVCR1), which is also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a TIM gene family member. In this study, we aimed to characterize the expression profile of HAVCR1 in GC, its prognostic value and the potential epigenetic mechanism leading to its dysregulation. Bioinformatic analysis was performed by using genomic, clinicopathological and survival data in the human protein atlas (HPA) and the Cancer Genome Atlas (TCGA). Results showed that HAVCR1 was significantly upregulated at the mRNA and protein level in GC tissues compared to the adjacent normal tissues. In addition, HAVCR1 upregulation was an independent indicator of shorter OS (HR: 1.698, 95%CI: 1.221–2.361, p = 0.002), after adjustment of older age, differentiation status, pathological stages and the presence of residual tumor and was also an independent indicator of shorter RFS (HR: 2.577, 95%CI: 1.583–4.197, p<0.001), after adjustment of gender and histological grade. The methylation level of two CpG sites (cg11188031 and cg07320595) was negatively correlated with HAVCR1 expression. However, only high methylation level of cg07320595 was associated with significantly longer OS (p = 0.018) and RFS (p = 0.021). Based on these findings, we infer that HAVCR1 upregulation might serve as a valuable prognostic marker in terms of OS and RFS in GC patients. Cg07320595 might be a critical CpG site influencing HAVCR1 expression.
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Affiliation(s)
- Lingling Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Zhaoquan Song
- Clinical Laboratory, Linyi Luozhuang Central Hospital, Linyi, Shandong, China
| | - Yingchun Zhao
- The 1 Ward of the Department of Paediatrics, Zhangqiu People’s Hospital, Jinan, Shandong, China
| | - Chao Li
- Department of NMR, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
- * E-mail:
| | - Hua Wei
- Department of Endoscopy, Huaihe Hospital, Henan University, Kaifeng, China
| | - Ji Ma
- Department of Endoscopy, Huaihe Hospital, Henan University, Kaifeng, China
| | - Yaowu Du
- Laboratory for Nanomedicine, School of Basic Medical Science, Henan University, Kaifeng, China
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23
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Shin EC, Jeong SH. Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a031708. [PMID: 29440324 DOI: 10.1101/cshperspect.a031708] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.
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Affiliation(s)
- Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seongnam, Gyeonggido 13620, Republic of Korea
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24
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Zhang Y, Li J, Li Q. Immune Evasion of Enteroviruses Under Innate Immune Monitoring. Front Microbiol 2018; 9:1866. [PMID: 30154774 PMCID: PMC6102382 DOI: 10.3389/fmicb.2018.01866] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 07/25/2018] [Indexed: 12/16/2022] Open
Abstract
As a major component of immunological defense against a great variety of pathogens, innate immunity is capable of activating the adaptive immune system. Viruses are a type of pathogen that proliferate parasitically in cells and have multiple strategies to escape from host immune pressure. Here, we review recent studies of the strategies and mechanisms by which enteroviruses evade innate immune monitoring.
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Affiliation(s)
- Ying Zhang
- Institute of Medical Biology, Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Jingyan Li
- Institute of Medical Biology, Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Qihan Li
- Institute of Medical Biology, Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
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Benjamin M, Agnihotry S, Srivastava A, Bolia R, Yachha SK, Aggarwal R. Relationship of Severity of Hepatitis A with Polymorphisms in Hepatitis A Virus Cellular Receptor 1 (HAVCR1) Gene. Ann Hepatol 2018; 17:561-568. [PMID: 29893695 DOI: 10.5604/01.3001.0012.0917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM HAVCR1 protein is the cellular receptor for hepatitis A virus (HAV). Genetic polymorphism in this gene may alter the outcome of HAV infection. In a previous study, a 6-amino acid insertion (157insMTTTVP) in HAVCR1 gene was associated with more severe disease. We decided to investigate this association further. MATERIAL AND METHODS We sequenced exon 4 of the HAVCR1 gene in patients with clinical hepatitis A attending our institution, and a group of healthy controls in a disease-endemic setting in India. Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms (indels; rs141023871 and rs139041445) were compared between patients and controls, as well as between patients with and without a severe form of disease (liver failure). RESULTS The gene had three haplotypes in the region of interest - a short form, an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion. The allele frequency (29/150 [19%] vs. 43/146 [29%]; p = ns) and haplotype frequency (29/75 [39%] vs. 39/73 [53%]; p = ns) of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls (30%). Further, the allele frequency (12/58 [21%] vs. 17/92 [18%]; p = ns) and haplotype frequency (12/29 [41%] vs.17/46 [37%]; p = ns) of the longest variant were also similar in patients with severe and mild disease. DISCUSSION In the study population, the 157insMTTTVP variant of HAVCR1 gene was not associated with more severe outcome of HAV infection. Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome.
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Affiliation(s)
- Mercilena Benjamin
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Shikha Agnihotry
- Biomedical Informatics Centre, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Rishi Bolia
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - S K Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India Biomedical Informatics Centre, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
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26
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HAVCR1 (CD365) and Its Mouse Ortholog Are Functional Hepatitis A Virus (HAV) Cellular Receptors That Mediate HAV Infection. J Virol 2018; 92:JVI.02065-17. [PMID: 29437974 DOI: 10.1128/jvi.02065-17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 01/31/2018] [Indexed: 12/12/2022] Open
Abstract
The hepatitis A virus (HAV) cellular receptor 1 (HAVCR1), classified as CD365, was initially discovered as an HAV cellular receptor using an expression cloning strategy. Due to the lack of HAV receptor-negative replication-competent cells, it was not possible to fully prove that HAVCR1 was a functional HAV receptor. However, biochemistry, classical virology, and epidemiology studies further supported the functional role of HAVCR1 as an HAV receptor. Here, we show that an anti-HAVCR1 monoclonal antibody that protected African green monkey kidney (AGMK) cells against HAV infection only partially protected monkey Vero E6 cells and human hepatoma Huh7 cells, indicating that these two cell lines express alternative yet unidentified HAV receptors. Therefore, we focused our work on AGMK cells to further characterize the function of HAVCR1 as an HAV receptor. Advances in clustered regularly interspaced short palindromic repeat/Cas9 technology allowed us to knock out the monkey ortholog of HAVCR1 in AGMK cells. The resulting AGMK HAVCR1 knockout (KO) cells lost susceptibility to HAV infection, including HAV-free viral particles (vpHAV) and exosomes purified from HAV-infected cells (exo-HAV). Transfection of HAVCR1 cDNA into AGMK HAVCR1 KO cells restored susceptibility to vpHAV and exo-HAV infection. Furthermore, transfection of the mouse ortholog of HAVCR1, mHavcr1, also restored the susceptibility of AGMK HAVCR1 KO cells to HAV infection. Taken together, our data clearly show that HAVCR1 and mHavcr1 are functional HAV receptors that mediate HAV infection. This work paves the way for the identification of alternative HAV receptors to gain a complete understanding of their interplay with HAVCR1 in the cell entry and pathogenic processes of HAV.IMPORTANCE HAVCR1, an HAV receptor, is expressed in different cell types, including regulatory immune cells and antigen-presenting cells. How HAV evades the immune response during a long incubation period of up to 4 weeks and the mechanism by which the subsequent necroinflammatory process clears the infection remain a puzzle that most likely involves the HAV-HAVCR1 interaction. Based on negative data, a recent paper from the S. M. Lemon and W. Maury laboratories (A. Das, A. Hirai-Yuki, O. Gonzalez-Lopez, B. Rhein, S. Moller-Tank, R. Brouillette, L. Hensley, I. Misumi, W. Lovell, J. M. Cullen, J. K. Whitmire, W. Maury, and S. M. Lemon, mBio 8:e00969-17, 2017, https://doi.org/10.1128/mBio.00969-17) suggested that HAVCR1 is not a functional HAV receptor, nor it is it required for HAV infection. However, our data, based on regain of the HAV receptor function in HAVCR1 knockout cells transfected with HAVCR1 cDNA, disagree with their findings. Our positive data show conclusively that HAVCR1 is indeed a functional HAV receptor and lays the ground for the identification of alternative HAV receptors and how they interact with HAVCR1 in cell entry and the pathogenesis of HAV.
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27
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Zhang X, Gu J, Zhou L, Mi QS. TIM-4 is expressed on invariant NKT cells but dispensable for their development and function. Oncotarget 2018; 7:71099-71111. [PMID: 27662666 PMCID: PMC5340118 DOI: 10.18632/oncotarget.12153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/12/2016] [Indexed: 11/25/2022] Open
Abstract
T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on antigen presenting cells, plays a versatile role in immunoregulation. CD1d-restricted invariant natural killer T (iNKT) cells are potent cells involved in the diverse immune responses. It was recently reported that recombinant TIM-4 (rTIM-4) alone enhanced cytokine production in NKT hybridoma, DN32.D3 cells. Hence, we hypothesized that TIM-4 might regulate iNKT cell biology, especially their function of cytokine secretion. For the first time, we identified that TIM-4 was expressed in thymus iNKT cells, and its expression increased upon iNKT cell migration to the secondary lymphoid organs, especially in lymph nodes. Using TIM-4-deficient mice, we found that lack of TIM-4 did not disturb iNKT cell development, maturation, peripheral homeostasis and cytokine secretion. Moreover, TIM-4 deficiency did not alter the polarization of iNKT sublineages, including NKT1, NKT2 and NKT17. Finally, the mixed bone marrow transfer experiments further confirmed normal iNKT cell development and function from TIM-4-deficient bone marrow. In conclusion, our data suggest that TIM-4 is expressed on iNKT cells but dispensable for their development and function.
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Affiliation(s)
- Xilin Zhang
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, United States of America.,Department of Dermatology, Henry Ford Health System, Detroit, MI, United States of America.,Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jun Gu
- Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Li Zhou
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, United States of America.,Department of Dermatology, Henry Ford Health System, Detroit, MI, United States of America.,Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.,Department of Immunology and Microbiology, Wayne State University School of Medicine, MI, United States of America
| | - Qing-Sheng Mi
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, United States of America.,Department of Dermatology, Henry Ford Health System, Detroit, MI, United States of America.,Department of Internal Medicine, Henry Ford Health System, Detroit, MI, United States of America.,Department of Immunology and Microbiology, Wayne State University School of Medicine, MI, United States of America
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Foster TL, Pickering S, Neil SJD. Inhibiting the Ins and Outs of HIV Replication: Cell-Intrinsic Antiretroviral Restrictions at the Plasma Membrane. Front Immunol 2018; 8:1853. [PMID: 29354117 PMCID: PMC5758531 DOI: 10.3389/fimmu.2017.01853] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/07/2017] [Indexed: 01/01/2023] Open
Abstract
Like all viruses, human immunodeficiency viruses (HIVs) and their primate lentivirus relatives must enter cells in order to replicate and, once produced, new virions need to exit to spread to new targets. These processes require the virus to cross the plasma membrane of the cell twice: once via fusion mediated by the envelope glycoprotein to deliver the viral core into the cytosol; and secondly by ESCRT-mediated scission of budding virions during release. This physical barrier thus presents a perfect location for host antiviral restrictions that target enveloped viruses in general. In this review we will examine the current understanding of innate host antiviral defences that inhibit these essential replicative steps of primate lentiviruses associated with the plasma membrane, the mechanism by which these viruses have adapted to evade such defences, and the role that this virus/host battleground plays in the transmission and pathogenesis of HIV/AIDS.
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Affiliation(s)
- Toshana L Foster
- Department of Infectious Disease, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Suzanne Pickering
- Department of Infectious Disease, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Stuart J D Neil
- Department of Infectious Disease, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
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29
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Lemon SM, Ott JJ, Van Damme P, Shouval D. Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention. J Hepatol 2017; 68:S0168-8278(17)32278-X. [PMID: 28887164 DOI: 10.1016/j.jhep.2017.08.034] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/30/2017] [Accepted: 08/30/2017] [Indexed: 02/08/2023]
Abstract
Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide prevalence and incidence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in the prevalence of HAV have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection, and review medical and public health aspects of immunisation and disease prevention.
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Affiliation(s)
- Stanley M Lemon
- Lineberger Comprehensive Cancer Center, and the Departments of Medicine and Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
| | - Jördis J Ott
- Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany.
| | - Pierre Van Damme
- Centre for the Evaluation of Vaccination, Vaccine & Infectious Disease Institute, Antwerp University, Antwerp, Belgium
| | - Daniel Shouval
- Liver Unit, Institute for Gastroenterology and Hepatology, Hadassah-Hebrew University Hospital, P.O.Box 12000, Jerusalem 91120, Israel
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30
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TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection. J Virol 2017; 91:JVI.01583-16. [PMID: 27807228 DOI: 10.1128/jvi.01583-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 10/20/2016] [Indexed: 02/08/2023] Open
Abstract
Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope. IMPORTANCE TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1 and its binding ligand, PS, may serve as novel targets for antiviral intervention.
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31
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32
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Penberthy KK, Ravichandran KS. Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 2016; 269:44-59. [PMID: 26683144 DOI: 10.1111/imr.12376] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Phosphatidylserine recognition receptors are a highly diverse set of receptors grouped by their ability to recognize the 'eat-me' signal phosphatidylserine on apoptotic cells. Most of the phosphatidylserine recognition receptors dampen inflammation by inducing the production of anti-inflammatory mediators during the phagocytosis of apoptotic corpses. However, many phosphatidylserine receptors are also capable of recognizing other ligands, with some receptors being categorized as scavenger receptors. It is now appreciated that these receptors can elicit different downstream events for particular ligands. Therefore, how phosphatidylserine recognition receptors mediate specific signals during recognition of apoptotic cells versus other ligands, and how this might help regulate the inflammatory state of a tissue is an important question that is not fully understood. Here, we revisit the work on signaling downstream of the phosphatidylserine recognition receptor BAI1, and evaluate how these and other signaling modules mediate signaling downstream from other receptors, including Stabilin-2, MerTK, and αvβ5. We also propose the concept that phosphatidylserine recognition receptors could be viewed as a subset of scavenger receptors that are capable of eliciting anti-inflammatory responses to apoptotic cells.
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Affiliation(s)
- Kristen K Penberthy
- Department of Microbiology, Immunology, and Cancer Biology, Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA
| | - Kodi S Ravichandran
- Department of Microbiology, Immunology, and Cancer Biology, Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA
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Thomas LJ, Vitale L, O'Neill T, Dolnick RY, Wallace PK, Minderman H, Gergel LE, Forsberg EM, Boyer JM, Storey JR, Pilsmaker CD, Hammond RA, Widger J, Sundarapandiyan K, Crocker A, Marsh HC, Keler T. Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1. Mol Cancer Ther 2016; 15:2946-2954. [PMID: 27671527 DOI: 10.1158/1535-7163.mct-16-0393] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 09/15/2016] [Accepted: 09/18/2016] [Indexed: 11/16/2022]
Abstract
T-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. TIM-1 expression is also upregulated in several human cancers, most notably in renal and ovarian carcinomas, but has very restricted expression in healthy tissues, thus representing a promising target for antibody-mediated therapy. To this end, we have developed a fully human monoclonal IgG1 antibody specific for the extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma), and A549 (human lung carcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and internalization was confirmed by quantitative imaging flow cytometry. An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to the potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1-expressing cell lines, but not on TIM-1-negative cell lines. Using the Caki-1, IGROV-1, and A549 xenograft mouse models, CDX-014 showed significant antitumor activity in a clinically relevant dose range. Safety evaluation in nonhuman primates has demonstrated a good profile and led to the initiation of clinical studies of CDX-014 in renal cell carcinoma and potentially other TIM-1-expressing tumors. Mol Cancer Ther; 15(12); 2946-54. ©2016 AACR.
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Affiliation(s)
| | | | | | - Ree Y Dolnick
- Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York
| | - Paul K Wallace
- Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York
| | - Hans Minderman
- Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York
| | | | | | | | | | | | | | | | | | | | | | - Tibor Keler
- Celldex Therapeutics, Inc., Hampton, New Jersey
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A 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 confers protections against HIV-1 infection. Microbes Infect 2016; 19:69-74. [PMID: 27652980 DOI: 10.1016/j.micinf.2016.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/13/2016] [Accepted: 09/14/2016] [Indexed: 11/23/2022]
Abstract
We investigated whether a 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 (T-cell immunoglobulin and mucin domain 1), modulates susceptibility to HIV-1 infection. The polymorphism was genotyped in three case/control cohorts of HIV-1 exposed seronegative individuals (HESN) and HIV-1 infected subjects from Italy, Peru, and Colombia; data from a Thai population were retrieved from the literature. Across all cohorts, homozygosity for the short TIM-1 allele was more common in HESNs than in HIV-1 infected subjects. A meta-analysis of the four association analyses yielded a p value of 0.005. In vitro infection assays of CD4+ T lymphocytes indicated that homozygosity for the short allele is associated with lower rate of HIV-1 replication. These results suggest that the deletion allele protects from HIV-1 infection with a recessive effect.
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Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, Harris E, Pereira L. Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. Cell Host Microbe 2016; 20:155-66. [PMID: 27443522 PMCID: PMC5257282 DOI: 10.1016/j.chom.2016.07.002] [Citation(s) in RCA: 361] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 07/07/2016] [Accepted: 07/08/2016] [Indexed: 12/13/2022]
Abstract
Zika virus (ZIKV) infection during pregnancy is linked to severe birth defects, but mother-to-fetus transmission routes are unknown. We infected different primary cell types from mid- and late-gestation placentas and explants from first-trimester chorionic villi with the prototype Ugandan and a recently isolated Nicaraguan ZIKV strain. ZIKV infects primary human placental cells and explants-cytotrophoblasts, endothelial cells, fibroblasts, and Hofbauer cells in chorionic villi and amniotic epithelial cells and trophoblast progenitors in amniochorionic membranes-that express Axl, Tyro3, and/or TIM1 viral entry cofactors. ZIKV produced NS3 and E proteins and generated higher viral titers in amniotic epithelial cells from mid-gestation compared to late-gestation placentas. Duramycin, a peptide that binds phosphatidylethanolamine in enveloped virions and precludes TIM1 binding, reduced ZIKV infection in placental cells and explants. Our results suggest that ZIKV spreads from basal and parietal decidua to chorionic villi and amniochorionic membranes and that targeting TIM1 could suppress infection at the uterine-placental interface.
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Affiliation(s)
- Takako Tabata
- Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthew Petitt
- Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Henry Puerta-Guardo
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Daniela Michlmayr
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Chunling Wang
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - June Fang-Hoover
- Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Eva Harris
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA.
| | - Lenore Pereira
- Department of Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, CA 94143, USA.
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Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling. Mediators Inflamm 2016; 2016:1759027. [PMID: 27578921 PMCID: PMC4989079 DOI: 10.1155/2016/1759027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/07/2016] [Accepted: 06/26/2016] [Indexed: 01/30/2023] Open
Abstract
We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein, in vitro stimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor gene HAVCR1/TIM-1 was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1.
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Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol 2016; 13:131-49. [PMID: 26837712 DOI: 10.1038/nrgastro.2015.219] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.
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Affiliation(s)
- Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India
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Abstract
PURPOSE OF REVIEW Transmission of hepatitis A virus (HAV) infection is primarily fecal-oral. Symptomatic hepatitis, severe disease, and death are more likely to occur when infection occurs at an older age. Improvements in socioeconomic and hygienic conditions have led to a change in its epidemiology worldwide. RECENT FINDINGS In the last two decades, improved hygiene in several resource-poor countries has led to reduced transmission of HAV, an increase in average age at infection, and, consequently, a paradoxical increase in morbidity and mortality because of hepatitis A. In Argentina, introduction of one dose (instead of the conventional two doses, to reduce costs) of inactivated HAV vaccine at 12-month age in a universal childhood immunization program during such 'epidemiologic transition' has markedly reduced the incidence of symptomatic hepatitis A, and of fulminant hepatitis and liver transplantation caused by HAV infection. The monetary value of medical and nonmedical benefits of this strategy outweighed the expenditure on vaccination. These excellent results were possibly contingent upon a high vaccination coverage. SUMMARY Resource-poor countries should closely monitor the epidemiology of HAV infection and periodically undertake cost-effectiveness analyses of HAV immunization strategies. This should allow timely identification of epidemiologic transition and introduction of preventive strategies before HAV infection becomes a public health problem.
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Xie X, Li C, Zhou B, Dai X, Rao L. Associations Between TIM1 Polymorphisms and Dilated Cardiomyopathy in a Han Chinese Population. Int Heart J 2016; 57:742-746. [PMID: 27818477 DOI: 10.1536/ihj.16-119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
| | - Chunmei Li
- Department of Cardiology, West China Hospital
| | - Bin Zhou
- Laboratory of Molecular Translational Medicine, West China Second University Hospital
| | - Xiaohui Dai
- Department of Cardiology, West China Hospital
| | - Li Rao
- Department of Cardiology, West China Hospital
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Trujillo-Ochoa JL, Corral-Jara KF, Escobedo-Meléndez G, Realpe M, Panduro A, Roman S, Fierro NA. T-helper 17-related cytokines and IgE antibodies during hepatitis A virus infection in children. Mem Inst Oswaldo Cruz 2015; 110:263-6. [PMID: 25946253 PMCID: PMC4489460 DOI: 10.1590/0074-02760140309] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 02/20/2015] [Indexed: 12/30/2022] Open
Abstract
We determined the serum IgE levels and T-helper (Th)17-related cytokines during
distinct hepatitis A virus (HAV)-induced clinical courses in children. A
significantly higher concentration of macrophage inflammatory protein 3α, interleukin
(IL)-17E and IL-17F in HAV-infected children with intermediate liver injury compared
with those with minor liver damage was found. A reduction in the IgE levels in those
patients who showed the highest levels of IL-17F in the group of intermediate liver
injury was found. The data suggested that the Th17-related profile is associated with
the severity of HAV infection and might play a role on the modulation achieved by HAV
during allergies.
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Affiliation(s)
| | | | | | - Mauricio Realpe
- Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
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41
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Walker CM, Feng Z, Lemon SM. Reassessing immune control of hepatitis A virus. Curr Opin Virol 2015; 11:7-13. [PMID: 25617494 DOI: 10.1016/j.coviro.2015.01.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 01/06/2015] [Indexed: 01/01/2023]
Abstract
There is renewed interest in hepatitis A virus (HAV) pathogenesis and immunity after 2-3 decades of limited progress. From a public health perspective, the average age at infection has increased in developing countries, resulting in more severe hepatitis that is poorly understood mechanistically. More fundamentally, there is interest in comparing immunity to HAV and hepatitis C virus (HCV): small, positive-strand RNA viruses with very different infection outcomes. Here, we review evidence that circulating HAV virions are cloaked in membranes, with consequences for induction of innate immunity and antibody-mediated neutralization. We also consider the contribution of CD4+ helper versus CD8+ cytotoxic T cells to antiviral immunity and liver injury, and present a model of non-cytotoxic immune control of HAV infection.
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Affiliation(s)
- Christopher M Walker
- Center for Vaccines and Immunity, Nationwide Children's Hospital, USA; College of Medicine, The Ohio State University, Columbus, OH 43205, USA
| | - Zongdi Feng
- Center for Vaccines and Immunity, Nationwide Children's Hospital, USA; College of Medicine, The Ohio State University, Columbus, OH 43205, USA
| | - Stanley M Lemon
- Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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42
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Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein. Trends Mol Med 2014; 20:675-84. [DOI: 10.1016/j.molmed.2014.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 09/30/2014] [Accepted: 10/13/2014] [Indexed: 12/30/2022]
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Kuroda M, Fujikura D, Noyori O, Kajihara M, Maruyama J, Miyamoto H, Yoshida R, Takada A. A polymorphism of the TIM-1 IgV domain: implications for the susceptibility to filovirus infection. Biochem Biophys Res Commun 2014; 455:223-8. [PMID: 25449273 PMCID: PMC7124303 DOI: 10.1016/j.bbrc.2014.10.144] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/29/2014] [Indexed: 01/17/2023]
Abstract
TIM-1 genes were compared among African green monkey kidney cell lines. Vero E6-derived TIM-1 has increased potential to promote filovirus entry. The IgV domain is primarily involved in TIM-1-mediated filovirus entry. A single amino acid in the IgV domain is crucial for the increased ability of TIM-1. TIM-1 polymorphism may affect the cell susceptibility to filovirus infection. Filoviruses, including Ebola and Marburg viruses, cause severe hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Human T-cell immunoglobulin and mucin domain 1 (TIM-1) is one of the host proteins that have been shown to promote filovirus entry into cells. In this study, we cloned TIM-1 genes from three different African green monkey kidney cell lines (Vero E6, COS-1, and BSC-1) and found that TIM-1 of Vero E6 had a 23-amino acid deletion and 6 amino acid substitutions compared with those of COS-1 and BSC-1. Interestingly, Vero E6 TIM-1 had a greater ability to promote the infectivity of vesicular stomatitis viruses pseudotyped with filovirus glycoproteins than COS-1-derived TIM-1. We further found that the increased ability of Vero E6 TIM-1 to promote virus infectivity was most likely due to a single amino acid difference between these TIM-1s. These results suggest that a polymorphism of the TIM-1 molecules is one of the factors that influence cell susceptibility to filovirus infection, providing a new insight into the molecular basis for the filovirus host range.
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Affiliation(s)
- Makoto Kuroda
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Daisuke Fujikura
- Division of Infection and Immunity, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Osamu Noyori
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Masahiro Kajihara
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Junki Maruyama
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Hiroko Miyamoto
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Reiko Yoshida
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan
| | - Ayato Takada
- Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan; Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 001-0020, Japan; School of Veterinary Medicine, The University of Zambia, P.O. Box 32379, Lusaka, Zambia.
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Abstract
OBJECTIVE Viral infections are often suspected to cause pediatric acute liver failure (PALF), but large-scale studies have not been performed. We analyzed the results of viral testing among nonacetaminophen PALF study participants. METHODS Participants were enrolled in the PALF registry. Diagnostic evaluation and final diagnosis were determined by the site investigator and methods for viral testing by local standard of care. Viruses were classified as either causative viruses (CVs) or associated viruses (AVs). Supplemental testing for CV was performed if not done clinically and serum was available. Final diagnoses included "viral," "indeterminate," and "other." RESULTS Of 860 participants, 820 had at least 1 test result for a CV or AV. A positive viral test was found in 166/820 (20.2%) participants and distributed among "viral" (66/80 [82.5%]), "indeterminate" (52/420 [12.4%]), and "other" (48/320 [15.0%]) diagnoses. CVs accounted for 81/166 (48.8%) positive tests. Herpes simplex virus (HSV) was positive in 39/335 (11.6%) who were tested 26/103 (25.2%) and 13/232 (5.6%) among infants 0 to 6 and >6 months, respectively. HSV was not tested in 61.0% and 53% of the overall cohort and those 0 to 6 months, respectively. Supplemental testing yielded 17 positive, including 5 HSV. CONCLUSIONS Viral testing in PALF occurs frequently but is often incomplete. The evidence for acute viral infection was found in 20.2% of those tested for viruses. HSV is an important viral cause for PALF in all age groups. The etiopathogenic role of CV and AV in PALF requires further investigation.
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Abstract
Hepatitis A virus (HAV) is a faeco-orally transmitted picornavirus and is one of the main causes of acute hepatitis worldwide. An overview of the molecular biology of HAV is presented with an emphasis on recent findings. Immune evasion strategies and a possible correlation between HAV and atopy are discussed as well. Despite the availability of efficient vaccines, antiviral drugs targeting HAV are required to treat severe cases of fulminant hepatitis, contain outbreaks, and halt the potential spread of vaccine-escape variants. Additionally, such drugs could be used to shorten the period of illness and decrease associated economical costs. Several known inhibitors of HAV with various mechanisms of action will be discussed. Since none of these molecules is readily useable in the clinic and since the availability of an anti-HAV drug would be of clinical importance, increased efforts should be targeted toward discovery and development of such antivirals.
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Affiliation(s)
- Yannick Debing
- Rega Institute for Medical ResearchUniversity of LeuvenLeuvenBelgium
| | - Johan Neyts
- Rega Institute for Medical ResearchUniversity of LeuvenLeuvenBelgium
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Abstract
Accumulating evidence indicates that T-cell immunoglobulin (Ig) and mucin domain (TIM) proteins play critical roles in viral infections. Herein, we report that the TIM-family proteins strongly inhibit HIV-1 release, resulting in diminished viral production and replication. Expression of TIM-1 causes HIV-1 Gag and mature viral particles to accumulate on the plasma membrane. Mutation of the phosphatidylserine (PS) binding sites of TIM-1 abolishes its ability to block HIV-1 release. TIM-1, but to a much lesser extent PS-binding deficient mutants, induces PS flipping onto the cell surface; TIM-1 is also found to be incorporated into HIV-1 virions. Importantly, TIM-1 inhibits HIV-1 replication in CD4-positive Jurkat cells, despite its capability of up-regulating CD4 and promoting HIV-1 entry. In addition to TIM-1, TIM-3 and TIM-4 also block the release of HIV-1, as well as that of murine leukemia virus (MLV) and Ebola virus (EBOV); knockdown of TIM-3 in differentiated monocyte-derived macrophages (MDMs) enhances HIV-1 production. The inhibitory effects of TIM-family proteins on virus release are extended to other PS receptors, such as Axl and RAGE. Overall, our study uncovers a novel ability of TIM-family proteins to block the release of HIV-1 and other viruses by interaction with virion- and cell-associated PS. Our work provides new insights into a virus-cell interaction that is mediated by TIMs and PS receptors.
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Long D, Fix OK, Deng X, Seielstad M, Lauring AS. Whole genome sequencing to identify host genetic risk factors for severe outcomes of hepatitis a virus infection. J Med Virol 2014; 86:1661-8. [PMID: 24978929 DOI: 10.1002/jmv.24007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2014] [Indexed: 01/10/2023]
Abstract
Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presentations of prevalent infections have often been attributed to pathogen-specific immune deficits that exhibit Mendelian inheritance. Genome-wide resequencing of unrelated cases has proven to be a powerful approach for identifying highly penetrant risk alleles that underlie such syndromes. Rare mutations likely to affect protein expression or function can be identified from sequence data, and their association with a similarly rare phenotype rests on their existence in multiple affected individuals. A rare or novel sequence variant that is enriched to a significant degree in a genetically diverse cohort suggests a candidate susceptibility allele. Whole genome sequencing of ten individuals from ethnically diverse backgrounds with HAV-associated acute liver failure was performed. A set of rational filtering criteria was used to identify genetic variants that are rare in the population, but enriched in this cohort. Single nucleotide polymorphisms, insertions, and deletions were considered and autosomal dominant, autosomal recessive, and polygenic models were applied. Analysis of the protein-coding exome identified no single gene with putatively deleterious mutations shared by multiple individuals, arguing against a simple Mendelian model of inheritance. A number of rare variants were significantly enriched in this cohort, consistent with a complex and genetically heterogeneous trait. Several of the variants identified in this genome-wide study lie within genes important to hepatic pathophysiology and are candidate susceptibility alleles for hepatitis A virus infection.
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Affiliation(s)
- Dustin Long
- Institute for Human Genetics, University of California at San Francisco, San Francisco, California
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Zheng K, Xu G, Lu X, Zhang J, Zhang P. Expression and polymorphisms of T cell immunoglobulin domain and mucin domain protein-1 in thymoma with or without myasthenia gravis. Oncol Lett 2014; 8:317-322. [PMID: 24959269 PMCID: PMC4063586 DOI: 10.3892/ol.2014.2090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 03/27/2014] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the expression and association of the single-nucleotide polymorphism (SNP) -1637A/G in the promoter region of the T cell immunoglobulin domain and mucin domain protein-1 (Tim-1) gene in patients diagnosed with thymoma with or without myasthenia gravis (MG). The expression of Tim-1 was detected using the streptavidin peroxidase immunohistochemical staining method on tissues obtained from thymoma patients with (n=58) and without (n=62) MG. The Tim-1 gene -1637A/G polymorphism was detected using the single allele-specific primer polymerase chain reaction. The positive rate of Tim-1 expression in thymoma patients with MG was 62.1% (32/58), which was significantly higher compared with that in thymoma patients without MG (33.9%, 21/62) (P=0.002). The genotype frequencies of GG, GA and AA in the -1637A/G polymorphism were 0.7931, 0.2069 and 0, respectively, in thymoma patients with MG, and 0.6129, 0.3871 and 0, respectively, in thymoma patients without MG. A significant difference in the genotypes between the thymoma patients with MG and those without MG was found (P=0.031). In addition, a significant difference in allele frequencies between thymoma patients with MG and those without MG (P=0.024) was observed. The high expression of Tim-1 in thymoma tissues may play an important role in the development of thymoma with MG. The -1637A/G polymorphism site of the promoter region in Tim-1 may be associated with thymoma with MG. These findings provide a basis for further genetic research of thymoma with MG.
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Affiliation(s)
- Kai Zheng
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Guowu Xu
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Xing Lu
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Jun Zhang
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
| | - Peng Zhang
- Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Heping, Tianjin 300052, P.R. China
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Hepatitis A virus: host interactions, molecular epidemiology and evolution. INFECTION GENETICS AND EVOLUTION 2013; 21:227-43. [PMID: 24200587 DOI: 10.1016/j.meegid.2013.10.023] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 10/25/2013] [Accepted: 10/26/2013] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis A virus (HAV) is the commonest viral cause of liver disease and presents an important public health problem worldwide. Several unique HAV properties and molecular mechanisms of its interaction with host were recently discovered and should aid in clarifying the pathogenesis of hepatitis A. Genetic characterization of HAV strains have resulted in the identification of different genotypes and subtypes, which exhibit a characteristic worldwide distribution. Shifts in HAV endemicity occurring in different parts of the world, introduction of genetically diverse strains from geographically distant regions, genotype displacement observed in some countries and population expansion detected in the last decades of the 20th century using phylogenetic analysis are important factors contributing to the complex dynamics of HAV infections worldwide. Strong selection pressures, some of which, like usage of deoptimized codons, are unique to HAV, limit genetic variability of the virus. Analysis of subgenomic regions has been proven useful for outbreak investigations. However, sharing short sequences among epidemiologically unrelated strains indicates that specific identification of HAV strains for molecular surveillance can be achieved only using whole-genome sequences. Here, we present up-to-date information on the HAV molecular epidemiology and evolution, and highlight the most relevant features of the HAV-host interactions.
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Vaughan G, Forbi JC, Xia GL, Fonseca-Ford M, Vazquez R, Khudyakov YE, Montiel S, Waterman S, Alpuche C, Gonçalves Rossi LM, Luna N. Full-length genome characterization and genetic relatedness analysis of hepatitis A virus outbreak strains associated with acute liver failure among children. J Med Virol 2013; 86:202-8. [PMID: 24243548 DOI: 10.1002/jmv.23843] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2013] [Indexed: 11/08/2022]
Affiliation(s)
- Gilberto Vaughan
- Division of Viral Hepatitis; Centers for Diseases Control and Prevention; Atlanta Georgia
| | - Joseph C. Forbi
- Division of Viral Hepatitis; Centers for Diseases Control and Prevention; Atlanta Georgia
| | - Guo-Liang Xia
- Division of Viral Hepatitis; Centers for Diseases Control and Prevention; Atlanta Georgia
| | - Maureen Fonseca-Ford
- Division of Global Migration and Quarantine; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Roberto Vazquez
- National Institute for Epidemiologic Diagnosis and Reference; Mexico City Mexico
| | - Yury E. Khudyakov
- Division of Viral Hepatitis; Centers for Diseases Control and Prevention; Atlanta Georgia
| | - Sonia Montiel
- Division of Global Migration and Quarantine; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Steve Waterman
- Division of Global Migration and Quarantine; Centers for Disease Control and Prevention; Atlanta Georgia
| | - Celia Alpuche
- National Institute for Epidemiologic Diagnosis and Reference; Mexico City Mexico
| | | | - Norma Luna
- General Directorate of Epidemiology; Mexico City Mexico
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