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postgraduate thesis: Impact of hepatitis E virus variants on human health

TitleImpact of hepatitis E virus variants on human health
Authors
Issue Date2021
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Sridhar, S.. (2021). Impact of hepatitis E virus variants on human health. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
Abstract´╗┐Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. Disease manifestations of hepatitis E range from subclinical infections to severe hepatitis. Hepatitis E in immunocompromised persons is often complicated by persistent infection that can lead to fibrosis and cirrhosis if left untreated. Conventionally, human hepatitis E is believed to be exclusively caused by genotypes within species A (HEV-A) of the Orthohepevirus genus of the family Hepeviridae. HEV-A genotypes 1 & 2 are transmitted from person-to-person in areas with poor sanitation while HEV-A swine genotypes 3 & 4 are acquired from undercooked pork products in developed regions. Orthohepevirus C (HEV-C) is a HEV species that circulates in rodents and ferrets. HEV-C is highly divergent from HEV-A. HEV-C genotype 1 (HEV-C1), also known as rat hepatitis E, is an ubiquitous pathogen of street rats across the world. Due to limited sequence identity with HEV-A and inability to infect non-human primates in experimental settings, HEV-C1 was hitherto considered incapable of infecting humans. Conventional molecular assays for hepatitis E completely miss HEV-C1 infections due to sequence divergence. In this thesis, HEV-C1 is definitively proven to be a novel cause of hepatitis in humans. A dedicated surveillance system using HEV-C1 nucleic acid amplification tests found frequent human infections across Hong Kong over several years of observation. HEV-C1 infected patients were frequently elderly and/or immunocompromised. Infections were concentrated in districts of the city with active HEV-C1 epizootics in the rat population. Evidence for transfusion-transmitted HEV-C1 infection is also presented illustrating its potential as a blood-borne pathogen. The clinical features of HEV-C1 and HEV-A infections were compared. Rat hepatitis E fully recapitulates the clinical features of HEV-A infection. Immunocompetent individuals usually suffered a mild self-limiting hepatitis, but some also demonstrated severe and relapsing hepatitis. Immunocompromised individuals routinely progressed to persistent infection and chronic hepatitis despite reduction in immunosuppression. Meningoencephalitis was documented as a possible extrahepatic manifestation of HEV-C1 infection. Oral ribavirin was usually effective at achieving sustained virological response in persistently infected individuals, but refractory disease was observed. Using a multimodal assessment, HEV-A and HEV-C1 were shown to be antigenically highly diverse. As commercial hepatitis E antigen and antibody assays are based on HEV-A, they were frequently insensitive for the diagnosis of HEV-C1 infection. A parallel immunoblot system using bespoke HEV-A and HEV-C1 peptides as capture antigens was able to differentiate HEV-A and HEV-C1 antibody signatures in infected patient sera with high accuracy. Furthermore, the same peptides formed virus like particles (VLPs) enabling them to be deployed as immunogenic vaccines. Vaccination with HEV-A VLPs was unable to protect experimental rats from a HEV-C1 virus challenge while the HEV-C1 VLP conferred sterilizing immunity against a heterotypic HEV-C1 strain challenge. This confirmed that HEV-A exposure is not cross-protective against HEV-C1 infection. Evidence of an anamnestic response to subsequent HEV-C1 infection in HEV-A vaccinated animals is presented. Overall, rat hepatitis E is a novel cause of human hepatitis, which represents a paradigm shift in the assumption that only HEV-A variants cause hepatitis E infection.
DegreeDoctor of Medicine
SubjectHepatitis E
Dept/ProgramMicrobiology
Persistent Identifierhttp://hdl.handle.net/10722/309720

 

DC FieldValueLanguage
dc.contributor.authorSridhar, Siddharth-
dc.date.accessioned2022-01-05T14:57:27Z-
dc.date.available2022-01-05T14:57:27Z-
dc.date.issued2021-
dc.identifier.citationSridhar, S.. (2021). Impact of hepatitis E virus variants on human health. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/309720-
dc.description.abstract´╗┐Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. Disease manifestations of hepatitis E range from subclinical infections to severe hepatitis. Hepatitis E in immunocompromised persons is often complicated by persistent infection that can lead to fibrosis and cirrhosis if left untreated. Conventionally, human hepatitis E is believed to be exclusively caused by genotypes within species A (HEV-A) of the Orthohepevirus genus of the family Hepeviridae. HEV-A genotypes 1 & 2 are transmitted from person-to-person in areas with poor sanitation while HEV-A swine genotypes 3 & 4 are acquired from undercooked pork products in developed regions. Orthohepevirus C (HEV-C) is a HEV species that circulates in rodents and ferrets. HEV-C is highly divergent from HEV-A. HEV-C genotype 1 (HEV-C1), also known as rat hepatitis E, is an ubiquitous pathogen of street rats across the world. Due to limited sequence identity with HEV-A and inability to infect non-human primates in experimental settings, HEV-C1 was hitherto considered incapable of infecting humans. Conventional molecular assays for hepatitis E completely miss HEV-C1 infections due to sequence divergence. In this thesis, HEV-C1 is definitively proven to be a novel cause of hepatitis in humans. A dedicated surveillance system using HEV-C1 nucleic acid amplification tests found frequent human infections across Hong Kong over several years of observation. HEV-C1 infected patients were frequently elderly and/or immunocompromised. Infections were concentrated in districts of the city with active HEV-C1 epizootics in the rat population. Evidence for transfusion-transmitted HEV-C1 infection is also presented illustrating its potential as a blood-borne pathogen. The clinical features of HEV-C1 and HEV-A infections were compared. Rat hepatitis E fully recapitulates the clinical features of HEV-A infection. Immunocompetent individuals usually suffered a mild self-limiting hepatitis, but some also demonstrated severe and relapsing hepatitis. Immunocompromised individuals routinely progressed to persistent infection and chronic hepatitis despite reduction in immunosuppression. Meningoencephalitis was documented as a possible extrahepatic manifestation of HEV-C1 infection. Oral ribavirin was usually effective at achieving sustained virological response in persistently infected individuals, but refractory disease was observed. Using a multimodal assessment, HEV-A and HEV-C1 were shown to be antigenically highly diverse. As commercial hepatitis E antigen and antibody assays are based on HEV-A, they were frequently insensitive for the diagnosis of HEV-C1 infection. A parallel immunoblot system using bespoke HEV-A and HEV-C1 peptides as capture antigens was able to differentiate HEV-A and HEV-C1 antibody signatures in infected patient sera with high accuracy. Furthermore, the same peptides formed virus like particles (VLPs) enabling them to be deployed as immunogenic vaccines. Vaccination with HEV-A VLPs was unable to protect experimental rats from a HEV-C1 virus challenge while the HEV-C1 VLP conferred sterilizing immunity against a heterotypic HEV-C1 strain challenge. This confirmed that HEV-A exposure is not cross-protective against HEV-C1 infection. Evidence of an anamnestic response to subsequent HEV-C1 infection in HEV-A vaccinated animals is presented. Overall, rat hepatitis E is a novel cause of human hepatitis, which represents a paradigm shift in the assumption that only HEV-A variants cause hepatitis E infection. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshHepatitis E-
dc.titleImpact of hepatitis E virus variants on human health-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Medicine-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineMicrobiology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2021-
dc.identifier.mmsid991044447546303414-

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