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León-Janampa N, Brand D, Marlet J. [Hepatitis E: Epidemiology, pathology and prevention]. Med Sci (Paris) 2025; 41:346-354. [PMID: 40294294 DOI: 10.1051/medsci/2025047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025] Open
Abstract
Hepatitis E virus (HEV) is a major cause of acute hepatitis. HEV genotypes 1 and 2 are associated with oro-faecal epidemics and fulminant hepatitis in pregnant women. HEV genotypes 3 and 4 are a zoonosis transmitted by uncooked pork. Infection is usually spontaneously resolutive. Chronic hepatitis may occur in immunocompromised patients. Extrahepatic disease is also possible. Prevention is based on hygiene, especially in high-risk patients, and access to safe drinking water for all. A recombinant vaccine against HEV has been developed and is currently being validated by the WHO.
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Affiliation(s)
- Nancy León-Janampa
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
| | - Denys Brand
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
| | - Julien Marlet
- INSERM U1259 MAVIVHe, Université de Tours et CHRU de Tours, Tours, France
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2
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Hu X, Wang J, Wang Y, Liu L, Miao J, Ren H, Wang J, Xu X. Uncovering the Prevalence and Genetic Characterization of Rabbit-Derived Paslahepevirus Balayani (Hepatitis E Virus) in Hebei Province, China. FOOD AND ENVIRONMENTAL VIROLOGY 2025; 17:20. [PMID: 40032702 DOI: 10.1007/s12560-025-09636-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
Paslahepevirus balayani (hepatitis E virus) is a zoonotic pathogen, with rabbit Paslahepevirus balayani (HEV-3ra) being widely distributed among global rabbit populations. Notably, in China, rabbits constitute a significant HEV host, second only to swine. Emerging evidence suggests that HEV-3ra possesses the capability to cross species barriers and infect humans. Against this backdrop, our investigation aimed to delineate the HEV infection status and epidemiological patterns in the commercial rabbits of Hebei Province, China. We collected 386 liver and 100 fecal samples across four regions in Hebei Province. Detection of HEV RNA in these specimens was achieved by employing reverse transcription quantitative polymerase chain reaction (RT-qPCR) and reverse transcription nested PCR (RT-Nested PCR), focusing on the amplification of a segment of the open reading frame 2 (ORF2) and the complete genome. Among the 486 samples, 73 were tested positive for HEV RNA, resulting in an overall positive rate of 15.0%. The positive rates for liver and fecal samples were 11.7% (45/386) and 28.0% (28/100), respectively. The study successfully obtained 38 partial ORF2 sequences and 5 complete genome sequences. Sequence analysis revealed that the complete genome sequences shared 86.0-94.5% nucleotide identity with HEV-3ra sequences in GenBank. Phylogenetic analysis confirmed that all strains belonged to HEV-3ra and were closely related to previously reported sequences from China. This study provides the first comprehensive genomic overview of circulating HEV-3ra strains in Hebei, offering valuable insights into the infection dynamics and prevalence of HEV-3ra among commercial rabbits, which can inform public health strategies.
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Affiliation(s)
- Xinyue Hu
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Jinfeng Wang
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
| | - Yinuo Wang
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Libing Liu
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051
| | - Junjie Miao
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Huan Ren
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017
| | - Jianchang Wang
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017.
- Food Microbiology and Animal Quarantine Laboratory, Technology Center of Shijiazhuang Customs, Shijiazhuang, China, 050051.
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017.
| | - Xiangdong Xu
- School of Public Health, Hebei Medical University, Shijiazhuang, China, 050017.
- Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, China, 050017.
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Kotb AA, El-Mokhtar MA, Sayed IM. Effect of Hepatitis E Virus on the Male Reproductive System: A Review of Current Evidence. Viruses 2025; 17:66. [PMID: 39861855 PMCID: PMC11768735 DOI: 10.3390/v17010066] [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: 12/10/2024] [Revised: 12/29/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Hepatitis E Virus (HEV) is a globally widespread pathogen that causes acute hepatitis infection. Beyond hepatic pathogenesis, HEV has been proven to cause several extrahepatic manifestations, such as neurological, renal, and hematological manifestations. It was also associated with mortality in pregnant females. Several studies have investigated the impact of HEV on the male reproductive system; however, the available data are limited and conflicting. Assessment of the patients' ejaculates/semen samples revealed that HEV particles are excreted in these fluids in cases of chronic infection but not acute infection. The excreted HEV particles are infectious to in vivo animal models and in vitro cell culture. However, the effect of HEV infection on male infertility is not confirmed. One study including human samples showed male infertility associated with HEV genotype 4 infection. Studies of HEV infection in animal models such as pigs, gerbils, and mice showed that HEV infection caused distortion on the testes, damage of the blood-testis barrier, and induction of inflammatory responses leading to abnormalities in the sperm. The excretion of HEV in the semen fluids raises concerns about HEV transmission via sexual transmission. However, all available data do not confirm the transmission of HEV through sexual intercourse. This review aims to summarize and critically assess the available studies investigating the influence of different HEV genotypes on the male reproductive system, providing insights into whether HEV contributes to reproductive impairment in men.
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Affiliation(s)
- Ahmed A. Kotb
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt;
| | - Mohamed A. El-Mokhtar
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos P.O. Box 36, Lebanon
| | - Ibrahim M. Sayed
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
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Elois MA, da Silva Grisard HB, Rodríguez-Lázaro D, Fongaro G. Challenges and global trends in combating enteric hepatitis. J Gen Virol 2024; 105. [PMID: 39693132 DOI: 10.1099/jgv.0.002059] [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] [Indexed: 12/19/2024] Open
Abstract
Enteric hepatitis, represented by the hepatitis A virus (HAV) and hepatitis E virus (HEV), remains a significant global public health concern. While much progress has been made, many aspects of the biology and pathophysiology of HAV and HEV are still not fully understood. One of the major challenges is the absence of a reliable system for virus replication. Additionally, the lack of standardized and widely accessible diagnostic tests contributes to the underestimation of the true prevalence of these viruses. Factors such as climate change, environmental shifts, globalization and increased population mobility further complicate the spread of these infections by affecting pathogen transmission, water quality and the distribution of vectors. This review approaches the emergent research challenges and trends of enteric hepatitis and focuses on developing more efficient diagnostic tools, exploring the role of zoonotic transmission and addressing the impact of environmental and climate changes on disease dynamics, underscoring the need for collaborative, interdisciplinary efforts to effectively combat enteric hepatitis in a rapidly changing world.
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Affiliation(s)
- Mariana Alves Elois
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
- Microbiology Division, Faculty of Sciences, University of Burgos, 09001 Burgos, Spain
- Research Centre for Emerging Pathogens and Global Health, University of Burgos, 09001 Burgos, Spain
| | - Henrique Borges da Silva Grisard
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
| | - David Rodríguez-Lázaro
- Microbiology Division, Faculty of Sciences, University of Burgos, 09001 Burgos, Spain
- Research Centre for Emerging Pathogens and Global Health, University of Burgos, 09001 Burgos, Spain
| | - Gislaine Fongaro
- Laboratory of Applied Virology, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil
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5
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Wei B, Li H, Cheng M, Yang Y, Liu B, Tian Y, Sun Y, Liu T, She R, Tian J. NLRP3 Inflammasome Activation Mediates Hepatitis E Virus-Induced Neuroinflammation. J Viral Hepat 2024; 31:729-738. [PMID: 39136210 DOI: 10.1111/jvh.13998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/17/2024] [Indexed: 10/23/2024]
Abstract
Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1β and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1β and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.
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Affiliation(s)
- Bingyan Wei
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Huopeng Li
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Minheng Cheng
- Beijing Center for Animal Disease Control and Prevention, Beijing, China
| | - Yifei Yang
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Bo Liu
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yuewei Tian
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yaxin Sun
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Tianlong Liu
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Ruiping She
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jijing Tian
- Laboratory of Animal Pathology and Public Health, National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
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Leblond AL, Helmchen B, Ankavay M, Lenggenhager D, Jetzer J, Helmchen F, Yurtsever H, Parrotta R, Healy ME, Pöschel A, Markkanen E, Semmo N, Ferrié M, Cocquerel L, Seeger H, Hopfer H, Müllhaupt B, Gouttenoire J, Moradpour D, Gaspert A, Weber A. HEV ORF2 protein-antibody complex deposits are associated with glomerulonephritis in hepatitis E with reduced immune status. Nat Commun 2024; 15:8849. [PMID: 39397005 PMCID: PMC11471813 DOI: 10.1038/s41467-024-53072-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 09/27/2024] [Indexed: 10/15/2024] Open
Abstract
Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications.
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Affiliation(s)
- Anne-Laure Leblond
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Birgit Helmchen
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Maliki Ankavay
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Jasna Jetzer
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Fritjof Helmchen
- Brain Research Institute, University of Zurich, Zurich, Switzerland
| | | | - Rossella Parrotta
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Marc E Healy
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Amiskwia Pöschel
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse Faculty, Zürich, Switzerland
| | - Enni Markkanen
- Institute of Veterinary Pharmacology and Toxicology, University of Zurich - Vetsuisse Faculty, Zürich, Switzerland
| | - Nasser Semmo
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Martin Ferrié
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Laurence Cocquerel
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Harald Seeger
- Clinic of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Helmut Hopfer
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jérôme Gouttenoire
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Ariana Gaspert
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University of Zurich (UZH) and University Hospital Zurich (USZ), Zurich, Switzerland.
- Institute of Molecular Cancer Research (IMCR), University of Zurich (UZH), Zurich, Switzerland.
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7
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He P, Li J, Wang C, Zhang J, Jiang Y, Liu H, Zhao Y, Li Z, Gao Y, Wang Y. Incidence and risk factors of de novo hepatitis E virus infection after receiving liver transplantation. J Med Virol 2024; 96:e29939. [PMID: 39360633 DOI: 10.1002/jmv.29939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
Organ transplant recipients with hepatitis E virus (HEV) infection bears high risk to develop chronic hepatitis, which is generally associated with immunosuppressive therapies. This study aimed to identify the incidence and predictors of de novo HEV infection in patients after receiving transplantation. We performed a large retrospective study to investigate the prevalence of anti-HEV at baseline, incidence of de novo HEV infection after transplantation, and the risk factors of HEV infection among patients with liver transplant in China. A total of 407 liver transplant recipients were examined for the presence of anti-HEV immunoglobulin G, IgM antibodies, and HEV RNA in serum. Basal indexes in individuals with evidence of post-transplant HEV infection were compared with those without evidence of that, and risk factors associated with HEV infection were assessed. The prevalence of anti-HEV at pretransplant in liver transplant recipients was 25.8% (105/407). Serum-negative conversion occurred in 34 (32.38%) of 105 liver transplant patients. Sixty-five out of 302 patients had de novo HEV infection after transplantation, with a cumulative incidence of 42.74% during follow-up. After transplantation, HEV infection was associated with liver failure (p = 0.012), hypoproteinemia (p = 0.030) and higher level of r-glutamyl transferase (GGT) (p = 0.022) before transplantation. Graft rejection (OR = 0.075; p = 0.045) was negatively associated with serum-negative conversion in patients who had positive anti-HEV antibody before transplantation. The incidence of de novo HEV infection after transplantation were higher in China. Liver failure, hypoproteinemia, and GGT elevation may be associated with HEV infection after liver transplantation. This study suggests that prevention and control of HEV infection after liver transplantation should be paid attention in patients bearing these risk factors.
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Affiliation(s)
- Ping He
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jialei Li
- Medical School of Nanjing University, Nanjing, China
| | - Chen Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Jiayue Zhang
- School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, China
| | - Yiyun Jiang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongyang Liu
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yao Zhao
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhiwei Li
- Department of Hepato-Biliary Surgery, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Yinjie Gao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yijin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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Liu T, He Q, Yang X, Li Y, Yuan D, Lu Q, Tang T, Guan G, Zheng L, Zhang H, Xia C, Yin X, Wei G, Chen X, Lu F, Wang L. An Immunocompetent Mongolian Gerbil Model for Hepatitis E Virus Genotype 1 Infection. Gastroenterology 2024; 167:750-763.e10. [PMID: 38582270 DOI: 10.1053/j.gastro.2024.03.038] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 03/18/2024] [Accepted: 03/27/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND & AIMS Hepatitis E virus (HEV), primarily genotype 1 (HEV-1), causes approximately 20.1 million infections, 44,000 deaths, and 3000 stillbirths annually. Current evidence indicates that HEV-1 is only transmitted in humans. Here, we evaluated whether Mongolian gerbils can serve as animal models for HEV-1 infection. METHODS Mongolian gerbils were used for HEV-1 and hepatitis E virus genotype 3 infection experiments. HEV infection parameters, including detection of HEV RNA and HEV antigen, liver function assessment, and histopathology, were evaluated. RESULTS We adapted a clinical isolate of HEV-1 for Mongolian gerbils by serial passaging in feces of aged male gerbils. The gerbil-adapted strain obtained at passage 3 induced a robust, acute HEV infection, characterized by stable fecal virus shedding, elevated liver enzymes, histopathologic changes in the liver, and seroconversion to anti-HEV. An infectious complementary DNA clone of the adapted virus was generated. HEV-1-infected pregnant gerbils showed a high rate of maternal mortality and vertical transmission. HEV RNA or antigens were detected in the liver, kidney, intestine, placenta, testis, and fetus liver. Liver and placental transcriptomic analyses indicated activation of host immunity. Tacrolimus prolonged HEV-1 infection, whereas ribavirin cleared infection. The protective efficacy of a licensed HEV vaccine was validated using this model. CONCLUSIONS HEV-1 efficiently infected Mongolian gerbils. This HEV-1 infection model will be valuable for investigating hepatitis E immunopathogenesis and evaluating vaccines and antivirals against HEV.
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Affiliation(s)
- Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xinyue Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuebao Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Disen Yuan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qinghui Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tianyu Tang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Guiwen Guan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Liwei Zheng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - He Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Changyou Xia
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xin Yin
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Guochao Wei
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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9
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Letafati A, Taghiabadi Z, Roushanzamir M, Memarpour B, Seyedi S, Farahani AV, Norouzi M, Karamian S, Zebardast A, Mehrabinia M, Ardekani OS, Fallah T, Khazry F, Daneshvar SF, Norouzi M. From discovery to treatment: tracing the path of hepatitis E virus. Virol J 2024; 21:194. [PMID: 39180020 PMCID: PMC11342613 DOI: 10.1186/s12985-024-02470-3] [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: 05/05/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.
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Affiliation(s)
- Arash Letafati
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
| | - Zahra Taghiabadi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mahshid Roushanzamir
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Department of Pharmacological and Biomolecular Science, University of Milan, Milan, Italy
| | - Bahar Memarpour
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
- Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Saba Seyedi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | | | - Masoomeh Norouzi
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Saeideh Karamian
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Arghavan Zebardast
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Marzieh Mehrabinia
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Omid Salahi Ardekani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Tina Fallah
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Fatemeh Khazry
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Samin Fathi Daneshvar
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Norouzi
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
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10
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He Q, Liu T, Yang X, Yuan D, Lu Q, Li Y, Zhang H, Liu X, Xia C, Sridhar S, Tian L, Liu X, Meng L, Ning J, Lu F, Wang L, Yin X, Wang L. Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits. J Virol 2024; 98:e0084624. [PMID: 38899900 PMCID: PMC11264948 DOI: 10.1128/jvi.00846-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.
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Affiliation(s)
- Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xinyue Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Disen Yuan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qinghui Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yuebao Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - He Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xing Liu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Changyou Xia
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lili Tian
- Miyun District Center for Disease Control and Prevention, Beijing, China
| | - Xiaofeng Liu
- Beijing Center for Disease Prevention and Control, Beijing, China
| | - Lulu Meng
- Beijing Center for Disease Prevention and Control, Beijing, China
| | - Jing Ning
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xin Yin
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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11
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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12
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Shahini E, Argentiero A, Andriano A, Losito F, Maida M, Facciorusso A, Cozzolongo R, Villa E. Hepatitis E Virus: What More Do We Need to Know? MEDICINA (KAUNAS, LITHUANIA) 2024; 60:998. [PMID: 38929615 PMCID: PMC11205503 DOI: 10.3390/medicina60060998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024]
Abstract
Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | | | - Alessandro Andriano
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy;
| | - Francesco Losito
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Marcello Maida
- Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, 93100 Caltanissetta, Italy;
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Erica Villa
- Gastroenterology Unit, CHIMOMO Department, University of Modena & Reggio Emilia, Via del Pozzo 71, 41121 Modena, Italy
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13
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Luo Q, Chen J, Zhang Y, Xu W, Liu Y, Xie C, Peng L. Viral hepatitis E: Clinical manifestations, treatment, and prevention. LIVER RESEARCH 2024; 8:11-21. [PMID: 39959034 PMCID: PMC11771268 DOI: 10.1016/j.livres.2024.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/17/2023] [Accepted: 01/03/2024] [Indexed: 02/18/2025]
Abstract
Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions. In the less developed regions of Asia and Africa, a high seropositivity rate has been reported for hepatitis E virus (HEV) antibodies. Although acute hepatitis E is often self-limited and has a favorable prognosis, some populations experience severe manifestations, which may progress to liver failure. Moreover, some immunocompromised patients are at risk of developing chronic HEV infection and cirrhosis. Proactive screening, reducing misdiagnosis, improving patient management, timely antiviral therapy for severe and chronic cases, and vaccination of high-risk groups are important measures to reduce the morbidity of hepatitis E. This review focused on the clinical presentation, management, and prevention of hepatitis E.
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Affiliation(s)
- Qiumin Luo
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jia Chen
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yeqiong Zhang
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenxiong Xu
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ying Liu
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chan Xie
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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14
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Tang ZM, Wen GP, Ying D, Wang SL, Liu C, Tian WK, Wang YB, Fang MJ, Zhou YL, Ge YS, Wu T, Zhang J, Huang SJ, Zheng ZZ, Xia NS. Profile of clinical characteristics and serologic markers of sporadic hepatitis E in a community cohort study. Emerg Microbes Infect 2023; 12:2140613. [PMID: 36314245 PMCID: PMC9769141 DOI: 10.1080/22221751.2022.2140613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis E virus (HEV) is a pathogen of global significance, but the value of HEV-related markers in the diagnosis of hepatitis E remains controversial. Previous studies on hepatitis E profiles have been mainly cross-sectional and conducted among inpatients in large hospitals, and hepatitis E cases have been primarily defined by limited partial markers. In this community-based study, 4,110 active hepatitis cases from a population of nearly 600,000 were followed over 48 months and serial serum samples were collected. Both HEV pathogen (HEV RNA and antigen) and anti-HEV antibody markers were used to determine HEV infection status and the relationship between hepatitis and HEV infection. In total, 98 hepatitis E patients were identified and all available isolates from 58 patients belonged to HEV genotype 4. The mean age of the patients was 58.14 years, with an overwhelming proportion of males (70.4%). Hepatitis E accounted for 22.86% of active hepatitis cases with alanine aminotransferase levels ≥15.0-fold the upper limit of normal, suggesting the need to include HEV in routine testing for these patients. Ninety-two hepatitis E patients were positive for at least 2 of HEV antigen, anti-HEV IgM, and HEV RNA markers at presentation, and 90.22% of them were positive for HEV antigen and anti-HEV IgM. HEV antigen, HEV RNA, and anti-HEV IgM positivity were observed in 89.80%, 82.65%, and 93.88% of hepatitis E patients at presentation, respectively. However, only 57.14% of anti-HEV IgM positivity occurred in hepatitis E patients. These findings will advance our understanding of hepatitis E and improve diagnosis.
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Affiliation(s)
- Zi-Min Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Gui-Ping Wen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Dong Ying
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,School of Life Sciences, Xiamen University, Xiamen, PR People’s Republic of China
| | - Si-Ling Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Wei-Kun Tian
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Ying-Bin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Mu-Jin Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Yu-Lin Zhou
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Yun-Sheng Ge
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Ting Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Shou-Jie Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 361102, China
| | - Zi-Zheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 361102, China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,School of Life Sciences, Xiamen University, Xiamen, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 361102, China
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15
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Stahl Y, Kabar I, Heinzow H, Maasoumy B, Bremer B, Wedemeyer H, Schmidt HHJ, Pietschmann T, Schlevogt B, Behrendt P. Enhanced monitoring and detection of recent genotype 3 hepatitis E virus infection through urine antigen testing. Emerg Microbes Infect 2023; 12:2251598. [PMID: 37649441 PMCID: PMC10512750 DOI: 10.1080/22221751.2023.2251598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/20/2023] [Indexed: 09/01/2023]
Abstract
Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis. Numerous studies have investigated the dynamics of HEV infection markers, but the most suitable marker for diagnosing ongoing or recent HEV infection remains to be determined. Recent evidence suggests that serum antigen testing is superior to serum IgM and RNA quantification. Moreover, it has been found that infected individuals excrete HEV antigen in significant quantities through urine. To address this question, we conducted a longitudinal analysis involving 16 patients with acute or chronic HEV infection in an area where genotype 3 HEV is prevalent. Our findings indicate that the diagnostic and monitoring capabilities of antigen testing for HEV infection can be further enhanced by measuring it in urine. Additionally, we were able to demonstrate that this enhancement is likely due to the presence of HEV-reactive IgG in blood plasma, which hampers efficient detection of HEV antigen through sandwich ELISA. In conclusion, urine-based antigen testing appears to be superior to measuring anti-HEV antibodies or viral RNA for diagnosing suspected HEV infection and monitoring ongoing infections.
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Affiliation(s)
- Yannick Stahl
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Iyad Kabar
- Department of Medicine B, Muenster University Hospital, Muenster, Germany
- Department for Internal Medicine, Raphaelsklinik Muenster, Muenster, Germany
| | - Hauke Heinzow
- Department of Medicine B, Muenster University Hospital, Muenster, Germany
- Medical Clinic I, Klinikum Der Barmherzigen Brüder Trier, Trier, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Disease and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner-site Hannover-Braunschweig, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology, Infectious Disease and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Disease and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner-site Hannover-Braunschweig, Hannover, Germany
- RESIST Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Hartmut H.-J. Schmidt
- Department of Medicine B, Muenster University Hospital, Muenster, Germany
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Thomas Pietschmann
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- German Centre for Infection Research (DZIF), partner-site Hannover-Braunschweig, Hannover, Germany
| | - Bernhard Schlevogt
- Department of Medicine B, Muenster University Hospital, Muenster, Germany
- Department of Gastroenterology, Medical Center Osnabrueck, Osnabrueck, Germany
| | - Patrick Behrendt
- Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Disease and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), partner-site Hannover-Braunschweig, Hannover, Germany
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16
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El-Mokhtar MA, Kamel AM, El-Sabaa EMW, Mandour SA, Abdelmohsen AS, Moussa AM, Salama EH, Aboulfotuh S, Abdel-Wahid L, Abdel Aziz EM, Azoz NMA, Sayed IM, Elkhawaga AA. Evidence of a Link between Hepatitis E Virus Exposure and Glomerulonephritis Development. Viruses 2023; 15:1379. [PMID: 37376678 DOI: 10.3390/v15061379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/07/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Viruses can trigger glomerulonephritis (GN) development. Hepatitis viruses, especially Hepatitis C virus and Hepatitis B viruses, are examples of the viruses that trigger GN initiation or progression. However, the proof of a correlation between GN and Hepatitis E virus infection is not clear. Some studies confirmed the development of GN during acute or chronic HEV infections, mainly caused by genotype 3. While others reported that there is no relation between HEV exposure and GN development. A recent study showed that a reduced glomerular filtration rate was developed in 16% of acute HEV genotype 1 (HEV-1) infections that returned to normal during recovery. HEV-1 is endemic in Egypt with a high seroprevalence among villagers and pregnant women. There is no available data about a link between HEV and GN in Egypt. METHODS GN patients (n = 43) and matched healthy subjects (n = 36) enrolled in Assiut University hospitals were included in this study. Blood samples were screened for hepatotropic pathogens. Tests for HEV markers such as HEV RNA and anti-HEV antibodies (IgM and IgG) were performed. Laboratory parameters were compared in HEV-seropositive and HEV-seronegative GN patients. RESULTS Anti-HEV IgG was detected in 26 (60.5%) out of 43 GN patients. HEV seroprevalence was significantly higher in GN than in healthy controls, suggesting that HEV exposure is a risk factor for GN development. None of the GN patients nor the healthy subjects were positive for anti-HEV IgM or HEV RNA. There was no significant difference between seropositive and seronegative GN patients in terms of age, gender, albumin, kidney function profiles, or liver transaminases. However, anti-HEV IgG positive GN patients had higher bilirubin levels than anti-HEV IgG negative GN patients. HEV-seropositive GN patients had a significantly elevated AST level compared to HEV-seropositive healthy subjects. CONCLUSION exposure to HEV infection could be complicated by the development of GN.
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Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Ayat M Kamel
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Ehsan M W El-Sabaa
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Sahar A Mandour
- Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia 11566, Egypt
| | - Ahmed Shawkat Abdelmohsen
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Abdelmajeed M Moussa
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Aswan University, Aswan 81528, Egypt
| | - Eman H Salama
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
| | - Sahar Aboulfotuh
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
| | - Lobna Abdel-Wahid
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Assiut University, Assiut 71515, Egypt
| | - Essam M Abdel Aziz
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Nashwa Mostafa A Azoz
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
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17
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Elkhawaga AA, El-Mokhtar MA, Mahmoud AA, Ali WE, Mohamed DS, Kamel AM, Mesalam AA, Mousa NHS, Ashmawy AM, Abdel Aziz EM, Sayed IM, Ramadan HKA, Elkholy YS. First Report on Abnormal Renal Function in Acute Hepatitis E Genotype 1 Infection. Pathogens 2023; 12:pathogens12050687. [PMID: 37242358 DOI: 10.3390/pathogens12050687] [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: 04/09/2023] [Revised: 04/28/2023] [Accepted: 04/29/2023] [Indexed: 05/28/2023] Open
Abstract
Impaired renal functions have been reported with Hepatitis E virus (HEV) infections, especially with genotypes 3 and 4. These complications were reported during the acute and chronic phases of infection. HEV genotype 1 causes acute infection, and the effect of HEV-1 infections on renal functions is not known. We examined the kidney function parameters in the serum of HEV-1 patients (AHE, n = 31) during the acute phase of infection. All of the included patients developed an acute self-limiting course of infection, without progression to fulminant hepatic failure. We compared the demographic, laboratory, and clinical data between AHE patients with normal kidney function parameters and those with abnormal renal parameters. Out of 31 AHE patients, 5 (16%) had abnormal kidney function tests (KFTs) during the acute phase of infection. Three patients had abnormal serum urea and creatinine, and two patients had either abnormal urea or creatinine. Four out of five patients had an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. AHE patients with abnormal KFTs were older and had a lower level of albumin, but a slightly elevated alanine transaminase (ALT) compared to AHE patients with normal KFTs. There were no significant differences between the two groups in terms of age, sex, liver transaminase levels, and the viral load. Similarly, the clinical presentations were comparable in both groups. Interestingly, these KFTs in patients with abnormal renal parameters returned to normal levels at the recovery. The serum creatinine level was not correlated with patients' age or liver transaminase levels, but it was significantly negatively correlated with albumin level. In conclusion, this study is the first report that evaluated KFTs in patients during the acute phase of HEV-1 infections. Impaired KFTs in some AHE patients resolved at convalescence. KFTs and renal complications should be monitored during HEV-1 infections.
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Affiliation(s)
- Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Amal A Mahmoud
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Wael Esmat Ali
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University Assuit Branch, Assiut 71524, Egypt
| | - Doaa Safwat Mohamed
- Department of Microbiology & Immunology, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt
| | - Ayat M Kamel
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Ahmed Atef Mesalam
- Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt
| | - Nermien H S Mousa
- Botany & Microbiology Department, Faculty of Science, Assiut University, Assiut 71515, Egypt
| | - Ahmed M Ashmawy
- Department of Internal Medicine, Gastroenterology and Hepatology Unit, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Essam M Abdel Aziz
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Yasmine Samy Elkholy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo 12613, Egypt
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18
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Urine: a place where HEV cannot hide! Hepatology 2023; 77:1475-1477. [PMID: 36626637 DOI: 10.1097/hep.0000000000000017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 09/26/2022] [Indexed: 01/12/2023]
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19
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Wang L, Wang Y, Zhuang H. Puzzles for Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:247-256. [PMID: 37223871 DOI: 10.1007/978-981-99-1304-6_17] [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 an important but understudied virus that has been the major cause of acute viral hepatitis worldwide. In recent decades, our understanding of this neglected virus has changed greatly: novel forms of viral proteins and their functions have been discovered; HEV can transmit via blood transfusion and organ transplantation; HEV can infect many animal species and the number is still increasing; HEV can induce chronic hepatitis and extra-hepatic manifestations. However, we are short of effective treatment measures to counter the virus. In this chapter we tend to briefly introduce the puzzles and major knowledge gaps existed in the field of HEV research.
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Affiliation(s)
- Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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20
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Geng Y, Shi T, Wang Y. Transmission of Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:73-92. [PMID: 37223860 DOI: 10.1007/978-981-99-1304-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Transmission of hepatitis E virus (HEV) occurs predominantly by the fecal-oral route. Large epidemics of hepatitis E in the developing countries of Asia and Africa are waterborne and spread through contaminated drinking water. The reservoir of HEV in developed countries is believed to be in animals with zoonotic transmission to humans, possibly through direct contact or the consumption of undercooked contaminated meat. And HEV transmission through blood transfusion, organ transplantation, and vertical transmission has been reported.
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Affiliation(s)
- Yansheng Geng
- Key Laboratory of Public Health Safety of Hebei Province, School of Public Health, Hebei University, Baoding, China
| | - Tengfei Shi
- Key Laboratory of Public Health Safety of Hebei Province, School of Public Health, Hebei University, Baoding, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China.
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21
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You S, Zhu B, Xin S. Clinical Manifestations of Hepatitis E. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:185-197. [PMID: 37223867 DOI: 10.1007/978-981-99-1304-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The clinical manifestations of hepatitis E are similar to those of other types of viral hepatitis. While acute hepatitis E is usually self-limited, pregnant women and chronic liver disease patients suffering from acute hepatitis E usually present with severe clinical manifestations that may develop into fulminant hepatic failure. Chronic HEV infection is typically seen in organ transplant patients; most HEV cases are asymptomatic and rarely display jaundice, fatigue, abdominal pain, fever, fatigue, or ascites. The clinical manifestations of HEV infection in neonates are diverse and have varied clinical signs, biochemistry, and virus-biomarkers. Lastly, the extrahepatic manifestations and complications of hepatitis E are in need of further study.
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Affiliation(s)
- Shaoli You
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Bing Zhu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shaojie Xin
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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22
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Zhao C, Wang Y. Laboratory Diagnosis of HEV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:199-213. [PMID: 37223868 DOI: 10.1007/978-981-99-1304-6_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Serological and nucleic acid tests for detecting hepatitis E virus (HEV) have been developed for both epidemiologic and diagnostic purposes. The laboratory diagnosis of HEV infection depends on the detection of HEV antigen or HEV RNA in the blood, stool, and other body fluids, and serum antibodies against HEV (immunoglobulin [Ig]A, IgM, and IgG). Anti-HEV IgM antibodies and low avidity IgG can be detected during the acute phase of the illness and can last approximately 12 months, representing primary infection, whereas anti-HEV IgG antibodies can last more than several years, representing remote exposure. Thus, the diagnosis of acute infection is based on the presence of anti-HEV IgM, low avidity IgG, HEV antigen, and HEV RNA, while epidemiological investigations are mainly based on anti-HEV IgG. Although significant progress has been made in developing and optimizing different formats of HEV assays, improving their sensitivity and specificity, there are many shortcomings and challenges in inter-assay concordance, validation, and standardization. This article reviews the current knowledge on the diagnosis of HEV infection, including the most common available laboratory diagnostic techniques.
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Affiliation(s)
- Chenyan Zhao
- 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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23
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Liu T, Wang L, Wang L. Animal Models for Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:171-184. [PMID: 37223866 DOI: 10.1007/978-981-99-1304-6_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Animal models are one of the most important tools in the study of human hepatitis E virus (HEV) infection. They are particularly important in light of the major limitations of the cell culture system for HEV. Besides nonhuman primates, which are extremely valuable because of their susceptibility to HEV genotypes 1-4, animals like swine, rabbit, and humanized mice are also potential models for studies of pathogenesis, cross-species infection, and the molecular biology of HEV. Identification of a useful animal model for human HEV infection studies is crucial to further investigations into this ubiquitous yet poorly understood virus and facilitate the development of antiviral therapeutics and vaccines.
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Affiliation(s)
- Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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24
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Zhou YH, Zhao H. Immunobiology and Host Response to HEV. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:93-118. [PMID: 37223861 DOI: 10.1007/978-981-99-1304-6_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) usually causes acute self-limiting hepatitis but sometimes leads to chronic infection in immunocompromised persons. HEV is not directly cytopathic. Immunologically mediated events after HEV infection are believed to play important roles in the pathogenesis and clearance of infection. The anti-HEV antibody responses have been largely clarified since the determination of major antigenic determinant of HEV, which is located in the C-terminal portion of ORF2. This major antigenic determinant also forms the conformational neutralization epitopes. Robust anti-HEV immunoglobulin M (IgM) and IgG responses usually develop 3-4 weeks after infection in experimentally infected nonhuman primates. In humans, potent specific IgM and IgG responses occur in the very early phase of the disease and are critical in eliminating the virus, in concert with the innate and adaptive T-cell immune responses. Testing anti-HEV IgM is valuable in the diagnosis of acute hepatitis E. The long-term persistence and protection of anti-HEV IgG provide the basis for estimating the prevalence of HEV infection and for the development of a hepatitis E vaccine. Although human HEV has four genotypes, all the viral strains are considered to belong to a single serotype. It is becoming increasingly clear that the innate and adaptive T-cell immune responses play critical roles in the clearance of the virus. Potent and multispecific CD4+ and CD8+ T cell responses to the ORF2 protein occur in patients with acute hepatitis E, and weaker HEV-specific CD4+ and CD8+ T cell responses appear to be associated with chronic hepatitis E in immunocompromised individuals.
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Affiliation(s)
- Yi-Hua Zhou
- Departments of Experimental Medicine and Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Hong Zhao
- Department of Infectious Diseases, Second Hospital of Nanjing, Southeast University School of Medicine, Nanjing, China
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25
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Risalde MA, Frias M, Caballero-Gómez J, Lopez-Lopez P, Fast C, Jiménez-Ruiz S, Agulló-Ros I, Eiden M, Jiménez-Martín D, García-Bocanegra I, Rivero A, Carlos Gómez Villamandos J, Rivero-Juarez A. Presence of hepatitis E virus in testis of naturally infected wild boars. Transbound Emerg Dis 2022; 69:3317-3324. [PMID: 35986711 PMCID: PMC10087141 DOI: 10.1111/tbed.14682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/25/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
Abstract
The hepatitis E virus (HEV) is the main cause of viral acute hepatitis in the world, affecting more than 20 million people annually. During the acute phase of infection, HEV can be detected in various body fluids, which has a significant impact in terms of transmission, diagnosis or extrahepatic manifestations. Several studies have isolated HEV in the genitourinary tract of humans and animals, which could have important clinical and epidemiological implications. So, our main objective was to evaluate the presence of HEV in testis of naturally infected wild boars (Sus scrofa). For it, blood, liver, hepatic lymph node and testicle samples were collected from 191 male wild boars. The presence of HEV was evaluated in serum by PCR, as well as in tissues by PCR and immunohistochemistry. Four animals (2.09%; 95%CI: 0.82-5.26) showed detectable HEV RNA in serum, being confirmed the presence of HEV-3f genotype in three of them by phylogenetic analysis. HEV was also detected in liver and/or hepatic lymph nodes of the four animals by RT-PCR, as well as by immunohistochemistry analysis. Only one of these wild boars also showed detectable viral load in testis, observing HEV-specific labelling in a small number of fibroblasts and some Sertoli cells. Our results confirm the presence of HEV genotype 3 in naturally infected wild boar testis, although no associated tissue damage was evidenced. This study does not allow us to discard semen as a possible source of HEV transmission in suids. Future experimental studies are necessary to evaluate the impact of HEV genotype 3 on fertility and the possibility of transmission through sexual contact in this specie.
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Affiliation(s)
- María A Risalde
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, Spain.,Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Mario Frias
- Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Javier Caballero-Gómez
- Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain.,Departamento de Sanidad Animal, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad animal, Córdoba, Spain
| | - Pedro Lopez-Lopez
- Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Christine Fast
- Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Greifswald-Insel, Riems, Germany
| | - Saúl Jiménez-Ruiz
- Departamento de Sanidad Animal, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad animal, Córdoba, Spain.,Grupo Sanidad y Biotecnología (SaBio), Instituto de Investigación en Recursos Cinegéticos IREC (UCLM-CSIC-JCCM), Universidad de Castilla-la Mancha (UCLM), Ciudad Real, Spain
| | - Irene Agulló-Ros
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, Spain
| | - Martin Eiden
- Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Greifswald-Insel, Riems, Germany
| | - Débora Jiménez-Martín
- Departamento de Sanidad Animal, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad animal, Córdoba, Spain
| | - Ignacio García-Bocanegra
- CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain.,Departamento de Sanidad Animal, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad animal, Córdoba, Spain
| | - Antonio Rivero
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, Spain.,Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain
| | - José Carlos Gómez Villamandos
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Grupo GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Antonio Rivero-Juarez
- Unidad de Enfermedades Infecciosas, Grupo de Virología Clínica y Zoonosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
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26
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Micro RNAs—The Small Big Players in Hepatitis E Virus Infection: A Comprehensive Review. Biomolecules 2022; 12:biom12111543. [PMID: 36358893 PMCID: PMC9687951 DOI: 10.3390/biom12111543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 12/02/2022] Open
Abstract
The molecular mechanism of hepatitis E virus (HEV) pathology is still unclear. The micro RNAs (miRNAs), of host or viral origin, interfere with virus replication and host environment in order to create an appropriate condition for the production of mature HEV progeny. Understanding the biogenesis and the interference of miRNAs with HEV will help to revile the mechanism of viral pathogenesis.
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27
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Virus-Associated Nephropathies: A Narrative Review. Int J Mol Sci 2022; 23:ijms231912014. [PMID: 36233315 PMCID: PMC9569621 DOI: 10.3390/ijms231912014] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/23/2022] [Accepted: 10/06/2022] [Indexed: 12/13/2022] Open
Abstract
While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.
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28
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Sayed IM, Karam-Allah Ramadan H, Hafez MHR, Elkhawaga AA, El-Mokhtar MA. Hepatitis E virus (HEV) open reading frame 2: Role in pathogenesis and diagnosis in HEV infections. Rev Med Virol 2022; 32:e2401. [PMID: 36209386 DOI: 10.1002/rmv.2401] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/12/2022]
Abstract
Hepatitis E virus (HEV) infection occurs worldwide. The HEV genome includes three to four open reading frames (ORF1-4). ORF1 proteins are essential for viral replication, while the ORF3 protein is an ion channel involved in the exit of HEV from the infected cells. ORF2 proteins form the viral capsid required for HEV invasion and assembly. They also suppress interferon production and inhibit antibody-mediated neutralisation of HEV, allowing the virus to hijack the host immune response. ORF2 is the only detectable viral protein in the human liver during HEV infection and it is secreted in the plasma, stool, and urine of HEV-infected patients, making it a reliable diagnostic marker. The plasma HEV ORF2 antigen level can predict the outcome of HEV infections. Hence, monitoring HEV ORF2 antigen levels may be useful in assessing the efficacy of anti-HEV therapy. The ORF2 antigen is immunogenic and includes epitopes that can induce neutralising antibodies; therefore, it is a potential HEV vaccine candidate. In this review, we highlighted the different forms of HEV ORF2 protein and their roles in HEV pathogenesis, diagnosis, monitoring the therapeutic efficacy, and vaccine development.
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Affiliation(s)
- Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud H R Hafez
- International Scholar, African Leadership Academy, Johannesburg, South Africa
| | - Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Microbiology and Immunology Department, Faculty of Pharmacy, Sphinx University, Assiut, Egypt
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29
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Ma Z, de Man RA, Kamar N, Pan Q. Chronic hepatitis E: Advancing research and patient care. J Hepatol 2022; 77:1109-1123. [PMID: 35605741 DOI: 10.1016/j.jhep.2022.05.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 12/15/2022]
Abstract
The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.
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Affiliation(s)
- Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Disease (Infinity), University Paul Sabatier, Toulouse, France
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
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A Secreted Form of the Hepatitis E Virus ORF2 Protein: Design Strategy, Antigenicity and Immunogenicity. Viruses 2022; 14:v14102122. [PMID: 36298677 PMCID: PMC9610824 DOI: 10.3390/v14102122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/10/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis E virus (HEV) is an important public health burden worldwide, causing approximately 20 million infections and 70,000 deaths annually. The viral capsid protein is encoded by open reading frame 2 (ORF2) of the HEV genome. Most ORF2 protein present in body fluids is the glycosylated secreted form of the protein (ORF2S). A recent study suggested that ORF2S is not necessary for the HEV life cycle. A previously reported efficient HEV cell culture system can be used to understand the origin and life cycle of ORF2S but is not sufficient for functional research. A more rapid and productive method for yielding ORF2S could help to study its antigenicity and immunogenicity. In this study, the ORF2S (tPA) expression construct was designed as a candidate tool. A set of representative anti-HEV monoclonal antibodies was further used to map the functional antigenic sites in the candidates. ORF2S (tPA) was used to study antigenicity and immunogenicity. Indirect ELISA revealed that ORF2S (tPA) was not antigenically identical to HEV 239 antigen (p239). The ORF2S-specific antibodies were successfully induced in one-dose-vaccinated BALB/c mice. The ORF2S-specific antibody response was detected in plasma from HEV-infected patients. Recombinant ORF2S (tPA) can act as a decoy to against B cells. Altogether, our study presents a design strategy for ORF2S expression and indicates that ORF2S (tPA) can be used for functional and structural studies of the HEV life cycle.
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Ying D, He Q, Tian W, Chen Y, Zhang X, Wang S, Liu C, Chen Z, Liu Y, Fu L, Yan L, Wang L, Tang Z, Wang L, Zheng Z, Xia N. Urine is a viral antigen reservoir in hepatitis E virus infection. Hepatology 2022; 77:1722-1734. [PMID: 36106666 DOI: 10.1002/hep.32745] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS HEV ORF2 antigen (Ag) in serum has become a tool for diagnosing current HEV infection. Particularly, urinary shedding of HEV Ag has been gaining increasing interest. We aim to uncover the origin, antigenicity, diagnostic performance, and diagnostic significance of Ag in urine in HEV infection. APPROACH AND RESULTS Clinical serum and urine samples from patients with acute and chronic HEV infection were analyzed for their Ag levels. Ag in urine was analyzed by biochemical and proteomic approaches. The origin of urinary Ag and Ag kinetics during HEV infection was investigated in mouse and rabbit models, respectively. We found that both the Ag level and diagnostic sensitivity in urine were higher than in serum. Antigenic protein in urine was an E2s-like dimer spanning amino acids 453-606. pORF2 entered urine from serum in mice i.v. injected with pORF2. Ag in urine originated from the secreted form of pORF2 (ORF2S ) that abundantly existed in hepatitis E patients' serum. HEV Ag was specifically taken up by renal cells and was disposed into urine, during which the level of Ag was concentrated >10-fold, resulting in the higher diagnosing sensitivity of urine Ag than serum Ag. Moreover, Ag in urine appeared 6 days earlier, lasted longer than viremia and antigenemia, and showed good concordance with fecal RNA in a rabbit model. CONCLUSIONS Our findings demonstrated the origin and diagnostic value of urine Ag and provided insights into the disposal of exogenous protein of pathogens by the host kidney.
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Affiliation(s)
- Dong Ying
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Weikun Tian
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Yanling Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Xiaoping Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Siling Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Zihao Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Yu Liu
- Department of Severe Hepatopathy, Shanghai Public Health Clinical Center, Fudan University, Shanghai, PR China
| | - Lijuan Fu
- Department of Infectious Disease, Xiang'an Hospital of Xiamen University, Xiamen, PR China
| | - Li Yan
- Department of Severe Hepatopathy, Shanghai Public Health Clinical Center, Fudan University, Shanghai, PR China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Zimin Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China.,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, PR China
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, PR China
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32
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He Q, Zhang F, Shu J, Li S, Liang Z, Du M, Liu X, Liu T, Li M, Yin X, Pan Q, Lu F, Wang L, Wang L. Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies. Hepatology 2022; 76:788-802. [PMID: 35278241 DOI: 10.1002/hep.32455] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/17/2022] [Accepted: 03/06/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings. APPROACH AND RESULTS Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit-derived HEV3 and human-derived HEV3 or HEV4). We assessed HEV markers within 13 weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T-cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses. CONCLUSIONS The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.
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Affiliation(s)
- Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fan Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingyi Shu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Shuangshuang Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhaochao Liang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Minghao Du
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xing Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Manyu Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xin Yin
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
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Takuissu GR, Kenmoe S, Ndip L, Ebogo-Belobo JT, Kengne-Ndé C, Mbaga DS, Bowo-Ngandji A, Oyono MG, Kenfack-Momo R, Tchatchouang S, Kenfack-Zanguim J, Lontuo Fogang R, Zeuko'o Menkem E, Kame-Ngasse GI, Magoudjou-Pekam JN, Nkie Esemu S, Veneri C, Mancini P, Bonanno Ferraro G, Iaconelli M, Suffredini E, La Rosa G. Hepatitis E Virus in Water Environments: A Systematic Review and Meta-analysis. FOOD AND ENVIRONMENTAL VIROLOGY 2022; 14:223-235. [PMID: 36036329 PMCID: PMC9458591 DOI: 10.1007/s12560-022-09530-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/21/2022] [Indexed: 06/01/2023]
Abstract
Hepatitis E virus (HEV) is responsible for acute hepatitis in humans, through foodborne, zoonotic, and waterborne transmission routes. This study aimed to assess the prevalence of HEV in water matrices. Six categories were defined: untreated and treated wastewater, surface water (river, lake, and seawater), drinking water, groundwater, and other water environments (irrigation water, grey water, reservoir water, flood water, and effluent of pig slaughterhouse). We searched PubMed, Web of Science, Global Index Medicus, and Excerpta Medica Database. Study selection and data extraction were performed by at least two independent investigators. Heterogeneity (I2) was assessed using the χ2 test on the Cochran Q statistic and H parameter. Sources of heterogeneity were explored by subgroup analysis. This study is registered with PROSPERO, number CRD42021289116. We included 87 prevalence studies from 58 papers, 66.4% of which performed in Europe. The overall prevalence of HEV in water was 9.8% (95% CI 6.4-13.7). The prevalence was higher in untreated wastewater (15.1%) and lower in treated wastewater (3.8%) and in drinking water (4.7%). In surface water, prevalence was 7.4%, and in groundwater, the percentage of positive samples, from only one study available, was 8.3%. Overall, only 36.8% of the studies reported the genotype of HEV, with genotype 3 (HEV-3) prevalent (168 samples), followed by HEV-1 (148 sample), and HEV-4 (2 samples). High-income countries were the most represented with 59/87 studies (67.8%), while only 3/87 (3.5%) of the studies were performed in low-income countries. The overall prevalence obtained of this study was generally higher in industrialized countries. Risk of bias was low in 14.9% of the studies and moderate in 85.1%. The results of this review showed the occurrence of HEV in different waters environments also in industrialized countries with sanitation and safe water supplies. While HEV transmission to humans through water has been widely demonstrated in developing countries, it is an issue still pending in industrialized countries. Better knowledge on the source of pollution, occurrence, survival in water, and removal by water treatment is needed to unravel this transmission path.
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Affiliation(s)
- G R Takuissu
- Centre for Food, Food Security and Nutrition Research, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | - S Kenmoe
- Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon
| | - L Ndip
- Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon
| | - J T Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | - C Kengne-Ndé
- Epidemiological Surveillance, Evaluation and Research Unit, National AIDS Control Committee, Douala, Cameroon
| | - D S Mbaga
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | - A Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | - M G Oyono
- Centre for Research on Health and Priority Pathologies, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | - R Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaoundé, Cameroon
| | - S Tchatchouang
- Scientific Direction, Centre Pasteur du Cameroun, Yaoundé, Cameroon
| | - J Kenfack-Zanguim
- Department of Biochemistry, The University of Yaounde I, Yaoundé, Cameroon
| | - R Lontuo Fogang
- Department of Animal Biology, University of Dschang, Dschang, Cameroon
| | - E Zeuko'o Menkem
- Department of Biomedical Sciences, University of Buea, Buea, Cameroon
| | - G I Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | | | - S Nkie Esemu
- Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon
| | - C Veneri
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - P Mancini
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - G Bonanno Ferraro
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - M Iaconelli
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy
| | - E Suffredini
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy
| | - G La Rosa
- Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy.
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Updates on hepatitis E virus. Chin Med J (Engl) 2022; 135:1231-1233. [PMID: 35787530 PMCID: PMC9337248 DOI: 10.1097/cm9.0000000000001998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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35
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Li M, Wang Y, Li K, Lan H, Zhou C. Characterization of highly expressed novel hub genes in hepatitis E virus chronicity in rabbits: a bioinformatics and experimental analysis. BMC Vet Res 2022; 18:239. [PMID: 35739587 PMCID: PMC9219159 DOI: 10.1186/s12917-022-03337-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatitis E virus (HEV), which is the leading cause of acute viral hepatitis worldwide, usually causes self-limited infections in common individuals. However, it can lead to chronic infection in immunocompromised individuals and its mechanisms remain unclear. Rabbits are the natural host of HEV, and chronic HEV infections have been observed in rabbits. Therefore, we aimed to investigate potential key genes in HEV chronicity process in rabbits. In this study, both bioinformatics and experimental analysis were performed to deepen the understanding of hub genes in HEV chronic infection in rabbits. RESULTS Ninety-four candidate differentially expressed genes (DEGs) and the pathways they enriched were identified to be related with HEV chronicity. A total of 10 hub genes were found by protein-protein interaction (PPI) network construction. Rabbits of group P (n = 4) which showed symptoms of chronic HEV infection were selected to be compared with HEV negative rabbits (group N, n = 6). By detecting the identified hub genes in groups P and N by real-time PCR, we found that the expressions of MX1, OAS2 and IFI44 were significantly higher in group P (P < 0.05). CONCLUSIONS In this work, we presented that MX1, OAS2 and IFI44 were significantly upregulated in HEV chronic infected rabbits, indicating that they may be involved in the pathogenesis of HEV chronicity.
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Affiliation(s)
- Manyu Li
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China.
| | - Yan Wang
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Kejian Li
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China
| | - Haiyun Lan
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China
| | - Cheng Zhou
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China.
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Characterization of Chronic Hepatitis E Virus Infection in Immunocompetent Rabbits. Viruses 2022; 14:v14061252. [PMID: 35746723 PMCID: PMC9229306 DOI: 10.3390/v14061252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 12/27/2022] Open
Abstract
Chronic hepatitis E virus (HEV) infection is frequently reported in immunocompromised patients, but has also been increasingly reported in non-immunocompromised individuals. We characterized the course of chronic HEV infection in immunocompetent rabbits. In two independent experiments, 40 specific-pathogen-free rabbits were infected with a rabbit HEV genotype 3 strain in serial diluted titers (108 to 104 copies/mL). Serum and fecal samples were collected weekly and were tested for HEV RNA, antigen, anti-HEV and liver enzymes. Rabbits that spontaneously cleared the infection before 10 weeks post-inoculation (wpi) were kept to the end of the study as recovery control. Liver tissues were collected from HEV-infected rabbits at 5, 10 and 26 wpi for histopathological analysis. Nineteen rabbits (47.5%) developed chronic HEV infection with persistent viraemia and fecal HEV shedding for >6 months. Seroconversion to anti-HEV was observed in 84.2% (16/19) of the chronically infected rabbits. Serum levels of aminotransferase were persistently elevated in most of the rabbits. Characterizations of chronic HEV infection in immunocompetent settings could be recapitulated in rabbits, which can serve as a valuable tool for future studies on pathogenesis.
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Jilani MG, Ali S. Assessment of simple sequence repeats signature in hepatitis E virus (HEV) genomes. J Genet Eng Biotechnol 2022; 20:73. [PMID: 35579724 PMCID: PMC9114184 DOI: 10.1186/s43141-022-00365-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022]
Abstract
Background Hepatitis E virus (HEV) is small (27–34 nm diameter) non-enveloped with positive sense ssRNA genome. Microsatellites or simple sequence repeats (SSR) are short tandem repeat sequences present across coding and non-coding regions of both prokaryotes and eukaryotes. They are involved with genome function and evolution at multiple levels. Results The complete genome sequences of 22 HEV genomes of the family Hepeviridae and genus Orthohepevirus (21 species) and Piscihepevirus (1 species) were extracted from NCBI database (http://www.ncbi.nlm.nih.gov/). The extraction of microsatellites was done using Imperfect Microsatellite Extractor (IMEx) in ‘Advance-Mode’. The average genome size of the studied HEV genomes was 7003nt and it ranged from 6649nt (HEV11) to 7310nt (HEV22). The average GC content of the genomes was ~ 55%. A total of 519 SSRs and 21 cSSRS were extracted from the HEV genomes with an average incidence of 24 per genome ranging from 14 (HEV13) to 34 (HEV19). The cSSR incidence ranged from 0 (eight species) to 4 (HEV19). The genomes with no cSSR incidence had an SSR incidence range from 14 to 28. There were just four hexa-nucleotide repeat motifs and 5 penta-nucleotide repeat motifs observed. The most prevalent mono-, di-, and tri-nucleotide repeat motifs were “C”, “GT/TG”, and “GAC/CTG” respectively. The studied genomes had a minimum of ~ 90% incident SSRs present in the coding regions. Viruses with same or similar hosts are placed together on the phylogenetic tree implicating viral host being one of the driving forces for evolution. Conclusions Host range in viruses is being decided by multiple factors aided by the unique genome SSR signature and genomes of varied compositions need to be analyzed to forge a widely acceptable rule for predicting the same. Supplementary Information The online version contains supplementary material available at 10.1186/s43141-022-00365-w.
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Affiliation(s)
- Md Gulam Jilani
- Clinical and Applied Genomics (CAG) Laboratory, Department of Biological Sciences, Aliah University, IIA/27, Newtown, Kolkata, 700160, India
| | - Safdar Ali
- Clinical and Applied Genomics (CAG) Laboratory, Department of Biological Sciences, Aliah University, IIA/27, Newtown, Kolkata, 700160, India.
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Kovvuru K, Carbajal N, Pakanati AR, Thongprayoon C, Hansrivijit P, Boonpheng B, Pattharanitima P, Nissaisorakarn V, Cheungpasitporn W, Kanduri SR. Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients. World J Hepatol 2022; 14:516-524. [PMID: 35582296 PMCID: PMC9055200 DOI: 10.4254/wjh.v14.i3.516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/04/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) infections are generally self-limited. Rare cases of hepatitis E induced fulminant liver failure requiring liver transplantation are reported in the literature. Even though HEV infection is generally encountered among developing countries, a recent uptrend is reported in developed countries. Consumption of unprocessed meat and zoonosis are considered to be the likely transmission modalities in developed countries. Renal involvement of HEV generally holds a benign and self-limited course. Although rare cases of cryoglobulinemia are reported in immunocompetent patients, glomerular manifestations of HEV infection are frequently encountered in immunocompromised and solid organ transplant recipients. The spectrum of renal manifestations of HEV infection include pre-renal failure, glomerular disorders, tubular and interstitial injury. Kidney biopsy is the gold standard diagnostic test that confirms the pattern of injury. Management predominantly includes conservative approach. Reduction of immunosuppressive medications and ribavirin (for 3-6 mo) is considered among patients with solid organ transplants. Here we review the clinical course, pathogenesis, renal manifestations, and management of HEV among immunocompetent and solid organ transplant recipients.
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Affiliation(s)
- Karthik Kovvuru
- Department of Medicine, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | - Nicholas Carbajal
- Department of Medicine, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
| | | | - Charat Thongprayoon
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, United States
| | - Panupong Hansrivijit
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Boonphiphop Boonpheng
- Department of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States
| | - Pattharawin Pattharanitima
- Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani 12121, Thailand
| | - Voravech Nissaisorakarn
- Department of Internal Medicine, MetroWest Medical Center, Tufts University School of Medicine, Boston, MA 01760, United States
| | | | - Swetha R Kanduri
- Department of Medicine, Ochsner Clinic Foundation, New Orleans, LA 70121, United States
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Liang Z, Shu J, He Q, Zhang F, Dai L, Wang L, Lu F, Wang L. High dose sofosbuvir and sofosbuvir-plus-ribavirin therapy inhibit Hepatitis E Virus (HEV) replication in a rabbit model for acute HEV infection. Antiviral Res 2022; 199:105274. [PMID: 35247472 DOI: 10.1016/j.antiviral.2022.105274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022]
Abstract
Hepatitis E virus (HEV) is an important cause of viral hepatitis worldwide and there is currently no FDA-approved anti-HEV drug. The commonly used drug ribavirin (RBV) could not achieve viral clearance in all patients and can induce drug resistance. Recent studies showed sofosbuvir (SOF) can inhibit HEV replication in vitro and has add-on effect when combined with RBV, but the effect of SOF against HEV infection remains controversial and the dosage of SOF warrants further exploration. In this study, a rabbit model for acute HEV infection was used to evaluate the effect of SOF at different doses against HEV genotype 3 and 4, and to compare the antiviral effect of SOF-plus-RBV therapy with RBV monotherapy. Virological parameters on fecal, serological and intrahepatic level were tested by real-time PCR and ELISA. Liver function tests and histopathological assays were performed. Both 200 mg/d and 300 mg/d SOF treatment inhibits HEV replication with relieved liver inflammation and declined levels of fecal HEV RNA, viremia and antigenemia. 300 mg/d SOF eliminated HEV replication while a short viral rebound was observed after 200 mg/d SOF treatment. The SOF-plus-RBV therapy also showed stronger anti-HEV effect than RBV monotherapy. Our study suggests that high dose of SOF showed better anti-HEV effect in the rabbit model. Moreover, the de novo SOF-plus-RBV therapy which eliminated acute HEV infection more efficiently than RBV monotherapy may serve as an alternative treatment strategy.
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Affiliation(s)
- Zhaochao Liang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingyi Shu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fan Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lizhong Dai
- Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China.
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China.
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Lack of Evidence for an Association between Previous HEV Genotype-3 Exposure and Glomerulonephritis in General. Pathogens 2021; 11:pathogens11010018. [PMID: 35055966 PMCID: PMC8779351 DOI: 10.3390/pathogens11010018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022] Open
Abstract
Among numerous other immune-mediated diseases, glomerulonephritis has also been suspected to be an extrahepatic manifestation of HEV infection. In this prospective study, we tested 108 patients with glomerulonephritis and 108 age- and sex-matched healthy controls at the University Hospital Hamburg Eppendorf, Hamburg, Germany, for anti-HEV IgG (Wantai test) as a marker for previous HEV exposure. A total of 24 patients (22%) tested positive for anti-HEV IgG. Males tended to be more frequently anti-HEV IgG positive (29%) in comparison to females (16%). However, this does not reach statistical significance (p = 0.07). Anti-HEV IgG positive patients were older in comparison to negative patients (mean 53 vs. 45 years, p = 0.05). The kidney function seems to be slightly decreased in anti-HEV IgG positive patients in comparison to and anti-HEV IgG negative patients basing on creatinine (p = 0.04) and glomerular filtration rate (GFR) (p = 0.05). Slightly higher values of bilirubin could be found in IgG positive patients (p = 0.04). Anti-HEV-IgG seropositivity rate (22%) in glomerulonephritis patients, did not differ significantly in comparison to an age- and sex-matched control cohort of healthy blood donors (31/108 positive, 29%). A total of 2/2 patients with membranoproliferative glomerulonephritis (MPGN) tested anti-HEV IgG positive (p = 0.002 in comparison to glomerulonephritis patients with other subtypes). In conclusion, our findings indicate that previous HEV exposure in a region where GT3 is endemic is not associated with glomerulonephritis in general. However, the subgroup of MPGN patients should be investigated in future studies. Furthermore, future studies are needed to investigate whether the observed association between anti-HEV IgG positivity and reduced GFR in glomerulonephritis patients is HEV associated or is an age-related effect.
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Zhou Z, Xie Y, Wu C, Nan Y. The Hepatitis E Virus Open Reading Frame 2 Protein: Beyond Viral Capsid. Front Microbiol 2021; 12:739124. [PMID: 34690982 PMCID: PMC8529240 DOI: 10.3389/fmicb.2021.739124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/20/2021] [Indexed: 12/20/2022] Open
Abstract
Hepatitis E virus (HEV) is a zoonotic pathogen causing hepatitis in both human and animal hosts, which is responsible for acute hepatitis E outbreaks worldwide. The 7.2 kb genome of the HEV encodes three well-defined open reading frames (ORFs), where the ORF2 translation product acts as the major virion component to form the viral capsid. In recent years, besides forming the capsid, more functions have been revealed for the HEV-ORF2 protein, and it appears that HEV-ORF2 plays multiple functions in both viral replication and pathogenesis. In this review, we systematically summarize the recent research advances regarding the function of the HEV-ORF2 protein such as application in the development of a vaccine, regulation of the innate immune response and cellular signaling, involvement in host tropism and participation in HEV pathogenesis as a novel secretory factor. Progress in understanding more of the function of HEV-ORF2 protein beyond the capsid protein would contribute to improved control and treatment of HEV infection.
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Affiliation(s)
- Zhaobin Zhou
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Yangling, China
| | - Yinqian Xie
- Shaanxi Animal Disease Prevention and Control Center, Xi’an, China
| | - Chunyan Wu
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Yangling, China
| | - Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Yangling, China
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42
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Yadav KK, Kenney SP. Hepatitis E Virus Immunopathogenesis. Pathogens 2021; 10:pathogens10091180. [PMID: 34578211 PMCID: PMC8465319 DOI: 10.3390/pathogens10091180] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/05/2021] [Accepted: 09/06/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus is an important emerging pathogen producing a lethal impact on the pregnant population and immunocompromised patients. Starting in 1983, it has been described as the cause for acute hepatitis transmitted via the fecal–oral route. However, zoonotic and blood transfusion transmission of HEV have been reported in the past few decades, leading to the detailed research of HEV pathogenesis. The reason behind HEV being highly virulent to the pregnant population particularly during the third trimester, leading to maternal and fetal death, remains unknown. Various host factors (immunological, nutritional, hormonal) and viral factors have been studied to define the key determinants assisting HEV to be virulent in pregnant and immunocompromised patients. Similarly, chronic hepatitis is seen particularly in solid organ transplant patients, resulting in fatal conditions. This review describes recent advances in the immunopathophysiology of HEV infections in general, pregnant, and immunocompromised populations, and further elucidates the in vitro and in vivo models utilized to understand HEV pathogenesis.
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Li S, He Q, Yan L, Li M, Liang Z, Shu J, Zhang F, Wang L, Wang L. Infectivity and pathogenicity of different hepatitis E virus genotypes/subtypes in rabbit model. Emerg Microbes Infect 2021; 9:2697-2705. [PMID: 33251979 PMCID: PMC7781933 DOI: 10.1080/22221751.2020.1858178] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The pathogenicity of each hepatitis E virus (HEV) genotypes/subtypes may be different. This study aimed to investigate the infectivity and pathogenicity of different HEV genotypes/subtypes from different mammalian sources especially human in rabbits, and to assess whether rabbits are an appropriate animal model to study different HEV genotypes/subtypes. Thirty-seven rabbits were randomly divided into nine groups and inoculated with eight different HEV strains, including human-derived HEV3b (hHEV-3b), hHEV-4a, hHEV-4d and hHEV-4h, swine-derived HEV4d (sHEV-4d) and sHEV-4h, rabbit-derived HEV3 (HEV-3ra) and camel-derived HEV8. HEV RNA, antigen, anti-HEV and alanine aminotransferase (ALT) in serum or/and feces were monitored weekly. One rabbit from each group was euthanized at seven weeks post inoculation and the liver specimens were taken for histopathological analysis and immunofluorescence staining of HEV ORF2 proteins. hHEV-4d, sHEV-4d and HEV-3ra infections were successfully established in rabbits and typical acute hepatitis symptoms were observed, including viraemia/antigenemia, fecal virus/antigen shedding, elevated ALT level and liver histopathological changes. One rabbit infected with HEV-3ra showed chronic infection. hHEV-4d and sHEV-4d are less infectious and pathogenic than HEV-3ra in rabbits. hHEV-3b and HEV8 only caused inapparent infection in rabbits as 60% (3/5) and 20% (1/5) of the rabbits seroconverted to anti-HEV, respectively. No obvious signs of HEV infection in rabbits inoculated with hHEV-4a, hHEV-4h and sHEV-4h. The infectivity and pathogenicity of different HEV genotypes/subtypes in rabbits is different, which may be related to the species specificity of HEV. Rabbit can be used as an animal model for the study of HEV-3ra and more importantly human HEV-4d.
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Affiliation(s)
- Shuangshuang Li
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Qiyu He
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Li Yan
- Department of Severe Hepatology, Shanghai Public Health Clinical Centre, Fudan University, Shanghai, People's Republic of China
| | - Manyu Li
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Zhaochao Liang
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Jingyi Shu
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Fan Zhang
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Centre, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
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Yang YL, Nan YC. Open reading frame 3 protein of hepatitis E virus: Multi-function protein with endless potential. World J Gastroenterol 2021; 27:2458-2473. [PMID: 34092969 PMCID: PMC8160619 DOI: 10.3748/wjg.v27.i20.2458] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/10/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV), a fecal-orally transmitted foodborne viral pathogen, causes acute hepatitis in humans and is responsible for hepatitis E outbreaks worldwide. Since the identification of HEV as a zoonotic agent, this virus has been isolated from a variety of hosts with an ever-expanding host range. HEV-open reading frame (ORF) 3, the smallest ORF in HEV genomes, initially had been perceived as an unremarkable HEV accessory protein. However, as novel HEV-ORF3 function has been discovered that is related to the existence of a putative third virion structural form, referred to as “quasi-enveloped” HEV particles, HEV is challenging the conventional virion structure-based classification scheme, which assigns all viruses to two groups, “enveloped” or “non-enveloped”. In this review, we systematically describe recent progress that has identified multiple pathogenic roles of HEV-ORF3, including roles in HEV virion release, biogenesis of quasi-enveloped virus, regulation of the host innate immune response, and interference with host signaling pathways. In addition, implications of HEV-ORF3-associated quasi-enveloped virions are discussed to guide future development of improved vaccines against zoonotic HEV infection.
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Affiliation(s)
- Yong-Lin Yang
- Department of Infectious Diseases, Taizhou People's Hospital, The Fifth Affiliated Hospital of Nantong University, Taizhou 225300, Jiangsu Province, China
- Department of General Practice, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
| | - Yu-Chen Nan
- Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi Province, China
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Meester M, Tobias TJ, Bouwknegt M, Kusters NE, Stegeman JA, van der Poel WHM. Infection dynamics and persistence of hepatitis E virus on pig farms - a review. Porcine Health Manag 2021; 7:16. [PMID: 33546777 PMCID: PMC7863251 DOI: 10.1186/s40813-021-00189-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 01/01/2021] [Indexed: 12/16/2022] Open
Abstract
Background Hepatitis E virus (HEV) genotype 3 and 4 is a zoonosis that causes hepatitis in humans. Humans can become infected by consumption of pork or contact with pigs. Pigs are the main reservoir of the virus worldwide and the virus is present on most pig farms. Main body Though HEV is present on most farms, the proportion of infected pigs at slaughter and thus the level of exposure to consumers differs between farms and countries. Understanding the cause of that difference is necessary to install effective measures to lower HEV in pigs at slaughter. Here, HEV studies are reviewed that include infection dynamics of HEV in pigs and on farms, risk factors for HEV farm prevalence, and that describe mechanisms and sources that could generate persistence on farms. Most pigs become infected after maternal immunity has waned, at the end of the nursing or beginning of the fattening phase. Risk factors increasing the likelihood of a high farm prevalence or proportion of actively infected slaughter pigs comprise of factors such as farm demographics, internal and external biosecurity and immunomodulating coinfections. On-farm persistence of HEV is plausible, because of a high transmission rate and a constant influx of susceptible pigs. Environmental sources of HEV that enhance persistence are contaminated manure storages, water and fomites. Conclusion As HEV is persistently present on most pig farms, current risk mitigation should focus on lowering transmission within farms, especially between farm compartments. Yet, one should be aware of the paradox of increasing the proportion of actively infected pigs at slaughter by reducing transmission insufficiently. Vaccination of pigs may aid HEV control in the future.
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Affiliation(s)
- M Meester
- Farm Animal Health unit, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
| | - T J Tobias
- Farm Animal Health unit, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | | | - N E Kusters
- Wageningen Bioveterinary Research, Lelystad, the Netherlands
| | - J A Stegeman
- Farm Animal Health unit, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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Ankcorn M, Said B, Morgan D, Elsharkawy AM, Maggs J, Ryder S, Valliani T, Gordon F, Abeysekera K, Suri D, McPherson S, Galliford J, Smith B, Pelosi E, Bansal S, Bethune C, Sheridan D, Vine L, Tedder RS, Ijaz S, Zuckerman M, Dalton H, Healy B, Donati M, Bicknell K, Evans C, Poller B, Smit E, Halsema C, Williams E, Raza M, McGann H, Irving W, Douthwaite S, Ch'ng CL, McCaughey C, Irish D. Persistent Hepatitis E virus infection across England and Wales 2009-2017: Demography, virology and outcomes. J Viral Hepat 2021; 28:420-430. [PMID: 33073452 DOI: 10.1111/jvh.13424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 01/11/2023]
Abstract
The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.
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Affiliation(s)
- Michael Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK
| | - Bengü Said
- Emerging Infections and Zoonoses, National Infection Service, Public Health England, London, UK
| | - Dilys Morgan
- Emerging Infections and Zoonoses, National Infection Service, Public Health England, London, UK
| | | | - James Maggs
- Department of Gastroenterology, Buckinghamshire Healthcare NHS Trust, Buckinghamshire, UK
| | - Stephen Ryder
- Department of Hepatology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Talal Valliani
- North Bristol Liver Unit, North Bristol NHS Trust, Southmead Hospital, Bristol, UK
| | - Fiona Gordon
- Department of Hepatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Kushala Abeysekera
- Department of Hepatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Deepak Suri
- Department of Hepatology, University College London Hospitals, London, UK
| | - Stuart McPherson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, & Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Jack Galliford
- Department of Nephrology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Belinda Smith
- Department of Hepatology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Emanuela Pelosi
- Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Sanjay Bansal
- Department of Paediatric Hepatology, Gastroenterology & Nutrition Center, King's College Hospital NHS Foundation Trust, London, UK
| | - Claire Bethune
- Department of Immunology and Allergy, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - David Sheridan
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Louisa Vine
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Richard S Tedder
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK.,Department of Medicine, Imperial College London, London, UK
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
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Development and Clinical Validation of a Pangenotypic PCR-Based Assay for the Detection and Quantification of Hepatitis E Virus ( Orthohepevirus A Genus). J Clin Microbiol 2021; 59:JCM.02075-20. [PMID: 33148702 DOI: 10.1128/jcm.02075-20] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/22/2020] [Indexed: 01/01/2023] Open
Abstract
The objective of this study was to design a pangenotypic PCR-based assay for the detection and quantification of hepatitis E virus (HEV) RNA from across the entire spectrum of described genotypes belonging to the Orthohepevirus A genus. The optimal conditions and the performance of the assay were determined by testing the WHO standard strain (6219/10) and the WHO HEV panel (8578/13). Similarly, performance comparisons were made with two commercial assays (Real Star HEV RT-PCR 2.0 and ampliCube HEV 2.0 Quant) to detect HEV RNA at concentrations below 1,000 IU/ml with viral strains from the WHO and to test samples from 54 patients with acute hepatitis. The assay presented in this study was able to detect the entire spectrum of described genotypes belonging to the Orthohepevirus A genus, demonstrating better performance than both commercial kits. This procedure may represent a significant improvement in the molecular diagnosis of HEV infection.
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48
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Dynamics of Hepatitis E Virus (HEV) Antibodies and Development of a Multifactorial Model To Improve the Diagnosis of HEV Infection in Resource-Limited Settings. J Clin Microbiol 2021; 59:JCM.02321-20. [PMID: 33239375 DOI: 10.1128/jcm.02321-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023] Open
Abstract
Serological markers are important for the diagnosis of hepatitis E virus (HEV) infection. This study aims to compare the diagnostic performance of the anti-HEV IgM and the HEV antigen (Ag) assays and establish a multifactorial model to improve the diagnosis of current HEV infection when HEV RNA detection is not available. A total of 809 serum samples, including 325 anti-HEV IgM-positive and 484 anti-HEV IgM-negative samples, were tested for HEV RNA. The anti-HEV IgM assay had very high sensitivity (99.4%) but moderate accuracy (79.2%) and specificity (74.3%). By retrospective follow-up of 58 patients with sequential samples (n = 143) tested for anti-HEV antibodies, we found anti-HEV IgM remained positive for more than 10 months in some HEV-infected patients, when HEV RNA was already undetectable; thus, decision solely based on anti-HEV IgM may lead to misdiagnosis. In contrast, the HEV Ag assay had very high specificity (100%). However, the detection efficiency of HEV Ag greatly diminished when the HEV RNA level was low or the anti-HEV IgG level was high. By logistic regression, a model integrating anti-HEV IgM, alanine aminotransferase, and HEV Ag was proposed, and the cutoff value was determined based on the testing results of the 143 sequential samples. The model was further evaluated with 67 randomly selected IgM-positive samples from single-visit patients. Overall, the model outperformed the anti-HEV IgM or the HEV Ag assay in the diagnosis of current HEV infection (sensitivity/specificity/accuracy, 89.5%/95.2%/91.9%). The area under the receiver operating characteristics curve of the model was greater than 0.97.
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El-Mokhtar MA, Sayed IM. Model systems for studying extrahepatic pathogenesis of hepatitis E virus. Current knowledge and future directions. Rev Med Virol 2021; 31:e2218. [PMID: 33475223 DOI: 10.1002/rmv.2218] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
Hepatitis E Virus is the most common cause of acute viral hepatitis globally. HEV infection is endemic in developing countries. Also, autochthonous and sporadic cases are reported in developed countries. HEV causes acute and chronic infections. Besides, extrahepatic manifestations including neurological, renal, haematological, acute pancreatitis and complications during pregnancy are associated with HEV infections. The pathogenesis of HEV in the extrahepatic tissues is either due to direct cytopathic effect mediated by the virus replication, or immunological mechanisms caused by an uncontrollable host response. Researchers have used different in vivo and in vitro models to study the pathogenesis of HEV in the extrahepatic tissues and analyse the host immune response against HEV infection. This review highlights the extrahepatic disorders associated with HEV infection. We focused on the in vivo and in vitro models as a tool for elucidating the HEV infection beyond the liver and studying the mechanisms of HEV induced tissue damages.
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Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Microbiology and Immunology Department, Faculty of Pharmacy, Sphinx University, Assiut, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Pathology, School of Medicine, University of California, San Diego La Jolla, California, USA
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50
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Lower Levels of Transaminases but Higher Levels of Serum Creatinine in Patients with Acute Hepatitis E in Comparison to Patients with Hepatitis A. Pathogens 2021; 10:pathogens10010060. [PMID: 33445435 PMCID: PMC7826713 DOI: 10.3390/pathogens10010060] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/29/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
In patients with hepatitis E virus (HEV) infections, extrahepatic, particularly renal and hematological manifestations, are increasingly reported in the medical literature but have never been studied compared to a control cohort. We retrospectively analyzed medical records of consecutive patients that were diagnosed with acute hepatitis E (AHE) (n = 69) or acute hepatitis A (AHA) (n = 46) at the University Medical Center Hamburg Eppendorf from January 2009 to August 2019 for demographical, clinical, and laboratory information. Patients with AHE had significantly lower median levels of ALAT (798 U/L) and total bilirubin (1.8 mg/dL) compared to patients with AHA (2326 U/L; p < 0.001 and 5.2 mg/dL; p < 0.001), suggesting a generally less severe hepatitis. In contrast, patients with AHE had significantly higher median serum creatinine levels (0.9 mg/dL vs. 0.8 mg/dL; p = 0.002) and lower median estimated glomerular filtration rate (eGFR) (91 mL/min/1.73 m2 vs. 109 mL/min/1.73 m2; p < 0.001) than patients with AHA. Leucocyte, neutrophil and lymphocyte count, hemoglobin, platelets, red cell distribution width (RDW), neutrophil to lymphocyte ratio (NLR), and RDW to lymphocyte ratio (RLR) did not differ between patients with AHE and those with AHA. Our observations indicate that renal but not hematological interference presents an underrecognized extrahepatic feature of AHE, while inflammation of the liver seems to be more severe in AHA.
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