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1
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Knol EF, van Neerven RJJ. IgE versus IgG and IgA: Differential roles of allergen-specific antibodies in sensitization, tolerization, and treatment of allergies. Immunol Rev 2024; 328:314-333. [PMID: 39285523 PMCID: PMC11659938 DOI: 10.1111/imr.13386] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
The prevalence of asthma, rhinitis, and food allergies has increased dramatically over the last few decades. This increase originally started in western countries, but is now also evident in many other regions of the world. Given the fact that the increase is so quick, the noted increase cannot be linked to a genetic effect, and many environmental factors have been identified that are associated with increased or reduced prevalence of allergies, like changing dietary habits, increased urbanization, pollution, exposure to microorganisms and LPS, and the farming environment and raw milk consumption. Although the key role of allergen-specific IgE in allergies is well known, the role of allergen-specific IgG and IgA antibodies is less well defined. This review will provide an overview of the functions of allergen-specific IgE in allergy, the role of allergen-specific antibodies (IgG (4) and IgA) in allergen immunotherapy (AIT), the possibility to use allergen-specific antibodies for treatment of ongoing allergies, and the potential role of allergen-specific antibodies in tolerance induction to allergens in a preventive setting. In the last, more speculative, section we will present novel hypotheses on the potential role of allergen-specific non-IgE antibodies in allergies by directing antigen presentation, Th2 development, and innate immune training.
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Affiliation(s)
- E. F. Knol
- Department of Dermatology/AllergologyUMC UtrechtUtrechtthe Netherlands
| | - R. J. J. van Neerven
- Cell Biology and ImmunologyWageningen University & ResearchWageningenthe Netherlands
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2
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Zhou Y, Zhao C, Tian Y, Xu N, Wang Y. Characteristics and Functions of HEV Proteins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:15-32. [PMID: 37223856 DOI: 10.1007/978-981-99-1304-6_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) is a non-enveloped virus containing a single-stranded, positive-sense RNA genome of 7.2 kb, which consists of a 5' non-coding region, three open reading frames (ORFs), and a 3' non-coding region. ORF1 is diverse between genotypes and encodes the nonstructural proteins, which include the enzymes needed for virus replication. In addition to its role in virus replication, the function of ORF1 is relevant to viral adaption in culture and may also relate to virus infection and HEV pathogenicity. ORF2 protein is the capsid protein, which is about 660 amino acids in length. It not only protects the integrity of the viral genome, but is also involved in many important physiological activities, such as virus assembly, infection, host interaction, and innate immune response. The main immune epitopes, especially neutralizing epitopes, are located on ORF2 protein, which is a candidate antigen for vaccine development. ORF3 protein is a phosphoprotein of 113 or 114 amino acids with a molecular weight of 13 kDa with multiple functions that can also induce strong immune reactivity. A novel ORF4 has been identified only in genotype 1 HEV and its translation promotes viral replication.
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Affiliation(s)
- Yan Zhou
- RegCMC, Great Regulatory Affairs, Sanofi (China) Investment Co., Ltd, Beijing, China
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Yabin Tian
- Division II of In Vitro Diagnostics for Infectious Diseases, National Institutes for Food and Drug Control, Beijing, China
| | - Nan Xu
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China.
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3
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Ishizaka A, Koga M, Mizutani T, Lim LA, Adachi E, Ikeuchi K, Ueda R, Aoyagi H, Tanaka S, Kiyono H, Matano T, Aizaki H, Yoshio S, Mita E, Muramatsu M, Kanto T, Tsutsumi T, Yotsuyanagi H. Prolonged Gut Dysbiosis and Fecal Excretion of Hepatitis A Virus in Patients Infected with Human Immunodeficiency Virus. Viruses 2021; 13:v13102101. [PMID: 34696531 PMCID: PMC8539651 DOI: 10.3390/v13102101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.
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Affiliation(s)
- Aya Ishizaka
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- Japan Foundation for AIDS Prevention, Tokyo 101-0064, Japan
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
| | - Taketoshi Mizutani
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- Correspondence: (T.M.); (H.Y.)
| | - Lay Ahyoung Lim
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
| | - Ryuta Ueda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Haruyo Aoyagi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Satoshi Tanaka
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; (S.T.); (E.M.)
| | - Hiroshi Kiyono
- International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan;
- CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines (cMAV), Department of Medicine, University of California San Diego, San Diego, CA 92093, USA
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
- Department of AIDS Vaccine Development, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan; (S.Y.); (T.K.)
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan; (S.T.); (E.M.)
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; (R.U.); (H.A.); (H.A.); (M.M.)
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan; (S.Y.); (T.K.)
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.)
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (L.A.L.); (E.A.); (K.I.)
- Correspondence: (T.M.); (H.Y.)
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Pintó RM, Pérez-Rodríguez FJ, Costafreda MI, Chavarria-Miró G, Guix S, Ribes E, Bosch A. Pathogenicity and virulence of hepatitis A virus. Virulence 2021; 12:1174-1185. [PMID: 33843464 PMCID: PMC8043188 DOI: 10.1080/21505594.2021.1910442] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatitis A is an acute infection of the liver, which is mostly asymptomatic in children and increases the severity with age. Although in most patients the infection resolves completely, in a few of them it may follow a prolonged or relapsed course or even a fulminant form. The reason for these different outcomes is unknown, but it is generally accepted that host factors such as the immunological status, age and the occurrence of underlaying hepatic diseases are the main determinants of the severity. However, it cannot be ruled out that some virus traits may also contribute to the severe clinical outcomes. In this review, we will analyze which genetic determinants of the virus may determine virulence, in the context of a paradigmatic virus in terms of its genomic, molecular, replicative, and evolutionary features.
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Affiliation(s)
- Rosa M Pintó
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Francisco-Javier Pérez-Rodríguez
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain.,Present Address: Division of Infectious Diseases, Laboratory of Virology, University of Geneva Hospitals, Geneva, Switzerland
| | - Maria-Isabel Costafreda
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Gemma Chavarria-Miró
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Susana Guix
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
| | - Enric Ribes
- Enteric Virus Laboratory, Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain
| | - Albert Bosch
- Enteric Virus Laboratory, Department of Genetics, Microbiology and Statistics, School of Biology, and Institute of Nutrition and Safety, University of Barcelona, Barcelona, Spain
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5
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Bove G, Mehnert AK, Dao Thi VL. iPSCs for modeling hepatotropic pathogen infections. IPSCS FOR STUDYING INFECTIOUS DISEASES 2021:149-213. [DOI: 10.1016/b978-0-12-823808-0.00013-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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6
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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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7
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Stuart DI, Ren J, Wang X, Rao Z, Fry EE. Hepatitis A Virus Capsid Structure. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031807. [PMID: 30037986 DOI: 10.1101/cshperspect.a031807] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis A virus (HAV) has been enigmatic, evading detailed structural analysis for many years. Its recently determined high-resolution structure revealed an angular surface without the indentations often characteristic of receptor-binding sites. The viral protein 1 (VP1) β-barrel shows no sign of a pocket factor and the amino terminus of VP2 displays a "domain swap" across the pentamer interface, as in a subset of mammalian picornaviruses and insect picorna-like viruses. Structure-based phylogeny confirms this placement. These differences suggest an uncoating mechanism distinct from that of enteroviruses. An empty capsid structure reveals internal differences in VP0 and the VP1 amino terminus connected with particle maturation. An HAV/Fab complex structure, in which the antigen-binding fragment (Fab) appears to act as a receptor-mimic, clarifies some historical epitope mapping data, but some remain difficult to reconcile. We still have little idea of the structural features of enveloped HAV particles.
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Affiliation(s)
- David I Stuart
- Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.,Diamond Light Source Ltd, Diamond House, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
| | - Jingshan Ren
- Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Xiangxi Wang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
| | - Zihe Rao
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.,Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Elizabeth E Fry
- Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
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8
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Muñoz-Martínez SG, Díaz-Hernández HA, Suárez-Flores D, Sánchez-Ávila JF, Gamboa-Domínguez A, García-Juárez I, Torre A. Atypical manifestations of hepatitis A virus infection. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2018; 83:134-143. [PMID: 29685743 DOI: 10.1016/j.rgmx.2017.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 09/13/2017] [Accepted: 10/05/2017] [Indexed: 02/07/2023]
Abstract
Acute hepatitis due to the hepatitis A virus usually has a short, benign and self-limited course, without causing chronic hepatitis. However, some cases have an atypical presentation, such as relapsing hepatitis, prolonged or persistent cholestasis, fulminant hepatic failure, or liver failure associated with autoimmune hepatitis. The typical clinical course of acute hepatitis A virus infection is spontaneous remission in 90% of the cases, but atypical cases have a prevalence that varies from less than 1 to 20%, depending on the manifestation (overall prevalence ∼7%). There is little information on the atypical clinical courses of hepatitis A virus infection and the lack of recognizing those presentations in clinical practice often results in carrying out numerous studies and treatments that not only are unnecessary, but can also be harmful. The aim of the present article was to describe 3 clinical cases of atypical hepatitis A infection and provide a literature review of such cases.
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Affiliation(s)
- S G Muñoz-Martínez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - H A Díaz-Hernández
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - D Suárez-Flores
- Departamento de Anatomía Patológica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - J F Sánchez-Ávila
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México; Unidad de Hepatología y Trasplante hepático, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - A Gamboa-Domínguez
- Departamento de Anatomía Patológica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - I García-Juárez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México; Unidad de Hepatología y Trasplante hepático, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - A Torre
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México; Unidad de Hepatología y Trasplante hepático, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.
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9
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10
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TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. mBio 2017; 8:mBio.00969-17. [PMID: 28874468 PMCID: PMC5587907 DOI: 10.1128/mbio.00969-17] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1−/− Ifnar1−/− and Tim4−/− Ifnar1−/− double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1−/− mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1−/−Ifnar1−/− mice compared to Ifnar1−/− mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice. T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than 2 decades ago to be an essential cellular receptor for hepatitis A virus (HAV), a picornavirus in the Hepatovirus genus, resulting in its designation as “hepatitis A virus cellular receptor 1” (HAVCR1) by the Human Genome Organization Gene Nomenclature Committee. However, recent studies have shown that HAV exists in nature as both naked, nonenveloped (HAV) virions and membrane-cloaked, quasi-enveloped infectious virus (eHAV), prompting us to revisit the role of TIM1 in viral entry. We show here that TIM1 (HAVCR1) is not an essential cellular receptor for HAV entry into cultured cells or required for viral replication and pathogenesis in permissive strains of mice, although it may facilitate early stages of infection by binding phosphatidylserine on the eHAV surface. This work thus corrects the published record and sets the stage for future efforts to identify specific hepatovirus entry factors.
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11
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Tian Y, Huang W, Yang J, Wen Z, Geng Y, Zhao C, Zhang H, Wang Y. Systematic identification of hepatitis E virus ORF2 interactome reveals that TMEM134 engages in ORF2-mediated NF-κB pathway. Virus Res 2017; 228:102-108. [PMID: 27899274 DOI: 10.1016/j.virusres.2016.11.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/18/2016] [Accepted: 11/18/2016] [Indexed: 01/08/2023]
Abstract
Hepatitis E virus (HEV) is the causative agent of acute hepatitis E. Open reading frame 2 (ORF2) encodes the capsid protein of HEV, which is the main structural protein and may participate, together with the host factors, in viral entry and egress. However, it is still not clear which host proteins are involved in the interaction with ORF2 and what the functions of these ORF2-interacting proteins are. In this study, we have applied a split-ubiquitin yeast two-hybrid screening approach in combination with the pull-down and coimmunoprecipitation assays, identified and validated multiple interacting partners of ORF2 of genotype 1 and 4, which have diverse biological functions. Among these novel candidates that have not been previously reported, we have found that 20 of them are located in endoplasmic reticulum. TMEM134, which interacts and co-localizes with ORF2 in the endoplasmic reticulum, negatively regulates ORF2-mediated inhibition of the NF-κB signaling pathway. Our study for the first time has systematically mapped the ORF2 interactome in two genotypes of HEV, providing a new insight of understanding the virus-host interaction during the pathogenesis of HEV, and may offer potential therapeutic targets to intervene the HEV life cycle.
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Affiliation(s)
- Yabin Tian
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Weijin Huang
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Jun Yang
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38015, USA.
| | - Zhiheng Wen
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Yansheng Geng
- Health Science Center, Hebei University, No. 342 Yuhuadonglu, Baoding 071000, China.
| | - Chenyan Zhao
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| | - Heqiu Zhang
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, 27, Taiping Road, Beijing 100850, China.
| | - Youchun Wang
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
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12
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Zhang L, Tian Y, Wen Z, Zhang F, Qi Y, Huang W, Zhang H, Wang Y. Asialoglycoprotein receptor facilitates infection of PLC/PRF/5 cells by HEV through interaction with ORF2. J Med Virol 2016; 88:2186-2195. [DOI: 10.1002/jmv.24570] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Li Zhang
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
| | - Yabin Tian
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
| | - Zhiheng Wen
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
| | - Feng Zhang
- Division of Monoclonal Antibody Products; National Institutes for Food and Drug Control; Beijing China
| | - Ying Qi
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
| | - Weijin Huang
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
| | - Heqiu Zhang
- Department of Bio-Diagnosis; Beijing Institute of Basic Medical Sciences; Beijing China
| | - Youchun Wang
- Division of HIV/AIDS and Sexually-Transmitted Virus Vaccines; National Institutes for Food and Drug Control; Beijing China
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13
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Specific IgA Enhances the Transcytosis and Excretion of Hepatitis A Virus. Sci Rep 2016; 6:21855. [PMID: 26911447 PMCID: PMC4766440 DOI: 10.1038/srep21855] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 02/02/2016] [Indexed: 12/23/2022] Open
Abstract
Hepatitis A virus (HAV) replicates in the liver, and is excreted from the body in feces. However, the mechanisms of HAV transport from hepatocytes to the gastrointestinal tract are poorly understood, mainly due to lack of suitable in vitro models. Here, we use a polarized hepatic cell line and in vivo models to demonstrate vectorial transport of HAV from hepatocytes into bile via the apical cell membrane. Although this transport is specific for HAV, the rate of fecal excretion in inefficient, accounting for less than 1% of input virus from the bloodstream per hour. However, we also found that the rate of HAV excretion was enhanced in the presence of HAV-specific IgA. Using mice lacking the polymeric IgA receptor (pIgR−/−), we show that a proportion of HAV:IgA complexes are transported via the pIgR demonstrating a role for specific antibody in pathogen excretion.
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14
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Zhou Y, Zhao C, Tian Y, Xu N, Wang Y. Characteristics and Functions of HEV Proteins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 948:17-38. [PMID: 27738977 DOI: 10.1007/978-94-024-0942-0_2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus (HEV) is a non-enveloped virus containing a single-stranded, positive-sense RNA genome of 7.2 kb, which consists of a 5' noncoding region, three open reading frames (ORFs), and a 3' noncoding region. ORF1 is diverse between genotypes and encodes the nonstructural proteins, which include the enzymes needed for virus replication. In addition to its role in virus replication, the function of ORF1 is relevant to viral adaption in cultured cells and may also relate to virus infection and HEV pathogenicity. ORF2 protein is the capsid protein, which is about 660 amino acids in length. It not only protects the integrity of the viral genome but is also involved in many important physiological activities, such as virus assembly, infection, and host interaction. The main immune epitopes, especially neutralizing epitopes, are located on ORF2 protein, which is a candidate antigen for vaccine development. ORF3 protein is a phosphoprotein of 113 or 114 amino acids with a molecular weight of 13 kDa with multiple functions that can also induce strong immune reactivity.
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Affiliation(s)
- Yan Zhou
- Division of Drug and Cosmetics Inspection, Center for Food and Drug Inspection, China Food and Drug Administration, No.11 Fa Hua Nan Li, Dongcheng District, Beijing, 100061, China
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China
| | - Yabin Tian
- Division of Diagnosis, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China
| | - Nan Xu
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China.
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15
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Karst SM. Identification of a novel cellular target and a co-factor for norovirus infection - B cells & commensal bacteria. Gut Microbes 2015; 6:266-71. [PMID: 25997033 PMCID: PMC4615308 DOI: 10.1080/19490976.2015.1052211] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Human noroviruses are a leading cause of gastroenteritis worldwide but research on these important enteric pathogens has long been restricted by their uncultivability. Extensive efforts to infect intestinal epithelial cells with murine and human noroviruses in vitro have been thus far unsuccessful while murine noroviruses efficiently and lytically infect innate immune cells including macrophages and dendritic cells. We have recently discovered that murine and human noroviruses infect B cells in vitro. The nature of B cell infection was distinct from innate immune cell infection in that mature B cells were infected noncytopathically in contrast to the lytic infection of macrophages and dendritic cells. Human norovirus infection of B cells was facilitated by commensal bacteria expressing an appropriate histo-blood group antigen. Importantly, we used the mouse model of norovirus infection to confirm that Peyer's patch B cells are infected, and that commensal bacteria stimulate infection, in vivo.
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Affiliation(s)
- Stephanie M Karst
- Molecular Genetics & Microbiology; University of Florida; Gainesville, FL USA,Correspondence to: Stephanie M Karst;
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16
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Wang X, Ren J, Gao Q, Hu Z, Sun Y, Li X, Rowlands DJ, Yin W, Wang J, Stuart DI, Rao Z, Fry EE. Hepatitis A virus and the origins of picornaviruses. Nature 2015; 517:85-88. [PMID: 25327248 PMCID: PMC4773894 DOI: 10.1038/nature13806] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 08/28/2014] [Indexed: 01/29/2023]
Abstract
Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually. It differs radically from other picornaviruses, existing in an enveloped form and being unusually stable, both genetically and physically, but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site, while structure-based predictions suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses, and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis.
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Affiliation(s)
- Xiangxi Wang
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
| | - Jingshan Ren
- Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK
| | - Qiang Gao
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
- Sinovac Biotech Co., Ltd., Beijing, 100085, China
| | - Zhongyu Hu
- National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing 100050, China
| | - Yao Sun
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
| | - Xuemei Li
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
| | - David J. Rowlands
- Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
| | - Weidong Yin
- Sinovac Biotech Co., Ltd., Beijing, 100085, China
| | - Junzhi Wang
- National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing 100050, China
| | - David I. Stuart
- Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK
- Diamond Light Sources, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
| | - Zihe Rao
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, 100101, China
- Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Elizabeth E. Fry
- Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK
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17
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Pintó RM, D'Andrea L, Pérez-Rodriguez FJ, Costafreda MI, Ribes E, Guix S, Bosch A. Hepatitis A virus evolution and the potential emergence of new variants escaping the presently available vaccines. Future Microbiol 2012; 7:331-46. [PMID: 22393888 DOI: 10.2217/fmb.12.5] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hepatitis A is the most common infection of the liver worldwide and is fecal-orally transmitted. Its incidence tends to decrease with improvements in hygiene conditions but at the same time its severity increases. Hepatitis A virus is the causative agent of acute hepatitis in humans and belongs to the Hepatovirus genus in the Picornaviridae family, and it has very unique characteristics. This article reviews some molecular and biological properties that allow the virus to live in a very quiescent way and to build an extremely stable capsid that is able to persist in and out of the body. Additionally, the relationship between the genomic composition and the structural and antigenic properties of the capsid is discussed, and the potential emergence of antigenic variants is evaluated from an evolutionary perspective.
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Affiliation(s)
- Rosa M Pintó
- Enteric Virus Laboratory, School of Biology, University of Barcelona, Barcelona, Spain.
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18
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Dotzauer A, Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012; 1:91-107. [PMID: 24175214 PMCID: PMC3782268 DOI: 10.5501/wjv.v1.i3.91] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 02/22/2012] [Accepted: 05/20/2012] [Indexed: 02/05/2023] Open
Abstract
Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.
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Affiliation(s)
- Andreas Dotzauer
- Andreas Dotzauer, Leena Kraemer, Department of Virology, University of Bremen, 28359 Bremen, Germany
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19
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Dotzauer A, Heitmann A, Laue T, Kraemer L, Schwabe K, Paulmann D, Flehmig B, Vallbracht A. The role of immunoglobulin A in prolonged and relapsing hepatitis A virus infections. J Gen Virol 2011; 93:754-760. [PMID: 22170633 DOI: 10.1099/vir.0.038406-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis A virus (HAV) infections result in different courses of the disease, varying between normal, prolonged and relapsing. However, the reason for these heterogeneous clinical appearances is not understood. As HAV-anti-HAV IgA immunocomplexes (HAV-IgA) infect hepatocytes, IgA was postulated as a carrier supporting hepatotropic transport of HAV, and it was speculated that this carrier mechanism contributes to the various clinical outcomes. In this study, the IgA-carrier mechanism was investigated in a mouse model. We show that HAV-IgA immunocomplexes efficiently reached the liver not only in HAV-seronegative mice, but also, and this is in contrast to free-HAV particles, in immunized HAV-seropositive animals. This IgA-mediated transport of HAV to the liver in the presence of immunity depended on the stage of development of the immune response. We conclude that over a period of several weeks after infection, anti-HAV IgA is able to promote an enterohepatic cycling of HAV, resulting in continuous endogenous reinfections of the liver. Our experiments indicate that highly avid IgG antibodies, which are present at later times of the infection, can terminate the reinfections. However, the endogenous reinfections in the presence of a developing neutralizing immunity might contribute to prolonged as well as to relapsing courses of HAV infections. Furthermore, the results show that serum IgA may act as an infection protracting factor.
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Affiliation(s)
- Andreas Dotzauer
- Department of Virology, University of Bremen, Leobener Straße/UFT, D-28359 Bremen, Germany
| | - Alke Heitmann
- QIAGEN Hamburg GmbH, Königstr. 4a, D-22767 Hamburg, Germany
| | - Thomas Laue
- Altona Diagnostics GmbH, Mörkenstr. 12, D-22767 Hamburg, Germany
| | - Leena Kraemer
- Department of Virology, University of Bremen, Leobener Straße/UFT, D-28359 Bremen, Germany
| | - Kerstin Schwabe
- Department of Neurosurgery, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
| | - Dajana Paulmann
- Department of Virology, University of Bremen, Leobener Straße/UFT, D-28359 Bremen, Germany
| | - Bertram Flehmig
- Children's Hospital, Department 1, University of Tübingen, Silcherstraße 7, D-72076 Tübingen, Germany
| | - Angelika Vallbracht
- Department of Virology, University of Bremen, Leobener Straße/UFT, D-28359 Bremen, Germany
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20
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Abstract
The cell imposes multiple barriers to virus entry. However, viruses exploit fundamental cellular processes to gain entry to cells and deliver their genetic cargo. Virus entry pathways are largely defined by the interactions between virus particles and their receptors at the cell surface. These interactions determine the mechanisms of virus attachment, uptake, intracellular trafficking, and, ultimately, penetration to the cytosol. Elucidating the complex interplay between viruses and their receptors is necessary for a full understanding of how these remarkable agents invade their cellular hosts.
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Affiliation(s)
- Joe Grove
- Cell Biology Unit, Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK.
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21
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Abstract
Hepatitis A virus (HAV) is an enterically transmitted virus that replicates predominantly in hepatocytes within the liver before excretion via bile through feces. Hepatocytes are polarized epithelial cells, and it has been assumed that the virus load in bile results from direct export of HAV via the apical domain of polarized hepatocytes. We have developed a subclone of hepatocyte-derived HepG2 cells (clone N6) that maintains functional characteristics of polarized hepatocytes but displays morphology typical of columnar epithelial cells, rather than the complex morphology that is typical of hepatocytes. N6 cells form microcolonies of polarized cells when grown on glass and confluent monolayers of polarized cells on semipermeable membranes. When N6 microcolonies were exposed to HAV, infection was restricted to peripheral cells of polarized colonies, whereas all cells could be infected in colonies of nonpolarized HepG2 cells (clone C11) or following disruption of tight junctions in N6 colonies with EGTA. This suggests that viral entry occurs predominantly via the basolateral plasma membrane, consistent with uptake of virus from the bloodstream after enteric exposure, as expected. Viral export was also found to be markedly vectorial in N6 but not C11 cells. However, rather than being exported from the apical domain as expected, more than 95% of HAV was exported via the basolateral domain of N6 cells, suggesting that virus is first excreted from infected hepatocytes into the bloodstream rather than to the biliary tree. Enteric excretion of HAV may therefore rely on reuptake and transcytosis of progeny HAV across hepatocytes into the bile. These studies provide the first example of the interactions between viruses and polarized hepatocytes.
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Abstract
Traditionally, the function of immunoglobulins A (IgA), the major type of secreted antibodies, has been thought to be restricted to binding antigens outside the epithelium basal membrane. Therefore, effector mechanisms eliminating IgA-opsonized targets have not been investigated so far. However, some indirect observations of infectious agents penetrating into tissues and blood from the environment suggest such mechanisms (analogous to IgG/IgM-dependent activation of complement and natural killers). In the present review, we examine details of IgA structure that might contribute to elucidation of IgA-dependent effector functions in human and animal immunity. Special attention is given to a putative transduction of signal about antigen binding in the active center of IgA from the Fab- to the Fc-superdomain via intramolecular conformational rearrangements. Different structure of the IgA subclasses (IgA1 and IgA2) is examined taking into account probable divergence of their functions in immune response.
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Affiliation(s)
- T N Kazeeva
- Bach Institute of Biochemistry, Russian Academy of Sciences, Moscow 119071, Russia
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23
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Tami C, Silberstein E, Manangeeswaran M, Freeman GJ, Umetsu SE, DeKruyff RH, Umetsu DT, Kaplan GG. Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions. J Virol 2007; 81:3437-46. [PMID: 17229699 PMCID: PMC1866050 DOI: 10.1128/jvi.01585-06] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The hepatitis A virus cellular receptor 1 (HAVCR1/TIM1), a member of the T-cell immunoglobulin mucin (TIM) family, is an important atopy susceptibility gene in humans. The exact natural function of HAVCR1/TIM1 and the inverse association between HAV infection and prevention of atopy are not well understood. To identify natural ligands of human HAVCR1/TIM1, we used an expression cloning strategy based on the binding of dog cells transfected with a human lymph node cDNA library to a HAVCR1/TIM1 Fc fusion protein. The transfected cells that bound to the human HAVCR1/TIM1 Fc contained cDNA of human immunoglobulin alpha 1 heavy (Igalpha1) and lambda light (Iglambda) chain and secreted human IgA1lambda antibody that bound to the cell surface. Cotransfection of the isolated Igalpha1 and Iglambda cDNAs to naïve dog cells resulted in the secretion of IgA1lambda that bound to HAVCR1/TIM1 Fc but not to a poliovirus receptor Fc fusion protein in a capture enzyme-linked immunosorbent assay. The interaction of HAVCR1/TIM1 with IgA was inhibited by monoclonal antibodies (MAbs) against Igalpha1 and Iglambda, excess IgA1lambda, or anti-HAVCR1/TIM1 MAb. IgA did not inhibit HAV infection of African green monkey cells, suggesting that the IgA and the virus binding sites are in different epitopes on HAVCR1/TIM1. IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1lambda is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions.
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Affiliation(s)
- Cecilia Tami
- Laboratory of Hepatitis and Related Emerging Agents, CBER, Food and Drug Administration, Bethesda, MD 20892, USA
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24
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Kusov YY, Zamjatina NA, Poleschuk VF, Michailov MI, Morace G, Eberle J, Gauss-Müller V. Immunogenicity of a chimeric hepatitis A virus (HAV) carrying the HIV gp41 epitope 2F5. Antiviral Res 2006; 73:101-11. [PMID: 17014915 DOI: 10.1016/j.antiviral.2006.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 06/27/2006] [Accepted: 08/04/2006] [Indexed: 10/24/2022]
Abstract
Its stable particle structure combined with its high immunogenicity makes the hepatitis A virus (HAV) a perfect carrier to expose foreign epitopes to the host immune system. In an earlier report [Beneduce, F., Kusov, Y., Klinger, M., Gauss-Müller, V., Morace, G., 2002. Chimeric hepatitis A virus particles presenting a foreign epitope (HIV gp41) at their surface. Antiviral Res. 55, 369-377] chimeric virus-like particles (HAV-gp41) were described that carried at their surface the dominant gp41 epitope 2F5 (2F5e) of the human immunodeficiency virus HIV-1. Extending this work, we now report that chimeric virus HAV-gp41 replicates in HAV-susceptible cells as well as in non-human primates. Infected marmosets developed both an anti-HAV and anti-2F5 epitope immune response. Furthermore, an HIV-neutralizing antibody response was elicited in guinea pigs immunized with HAV-gp41 chimeric particles. The results demonstrate that the replication-competent chimeric HAV-gp41 can serve as either a live or a subunit vaccine for eliciting of antibodies directed against a foreign antigenic epitope.
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Affiliation(s)
- Yuri Y Kusov
- Institute of Medical Molecular Biology, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
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