Special Issue "Hepatitis E Virus (HEV) Infections"

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: 31 July 2020.

Special Issue Editor

Prof. Dr. C. Thomas Bock
Website
Guest Editor
Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
Interests: Molecular virology; Hepatitis E virus

Special Issue Information

Dear Colleagues

Hepatitis E virus (HEV) is the predominant cause of an enterically acquired acute viral hepatitis with an estimated 20 million infections worldwide and 44,000 associated deaths each year. HEV is highly endemic in resource limited countries where the virus is spread through the fecal-oral route during large waterborne outbreaks. Current HEV outbreaks of 2018/2019 were reported to the World Health Organisation (WHO) from West-Africa. HEV is increasingly recognized as an emerging disease in industrialized nations since an increasing number of locally acquired (autochthone) human hepatitis E cases has been recognized raising considerable concern. In addition to the water-/food borne associated transmission pattern there is clear evidence indicating that HEV is a zoonotic pathogen, which can infect humans through consumption of undercooked meat of infected domestic pigs and wild animals. Therefore, it has become evident that the disease may represent a significant global health burden.

However, the understanding of the zoonotic potential and detailed epidemiological data of HEV infections is still improvable.

The course of HEV infection in immunocompetent individuals is most often asymptomatic. When presenting with symptoms, hepatitis E usually manifests as a mild and self-limiting disease; however, the overall mortality rate may be 1-3% in general populations. Certain risk populations such as persons with pre-existing liver diseases and pregnant women may develop severe complications including fulminant hepatic failure, pre-term labor and increased incidence of fetal and maternal death with a fatality rate of up to 30%.

The mechanisms leading to different clinical outcome of HEV infection especially in pregnant is not well understood and needs further input and investigation.

In immunocompromised persons, such as solid organ and hematopoietic stem cell transplant recipients, HEV infections can develop into a chronic progression and affected patients may have worse prognoses. Although the antiviral drug ribavirin (RBV) is used as an off-label treatment to a degree of success in treated patients, side effects often pose limitations. Prolonged treatment can select viral mutants that are less susceptible to RBV. Predicting chronicity of HEV infection, i.e., with characteristic biomarkers, and thus administering antiviral therapy as early as possible would pose a valuable opportunity for increased patient care and control of disease outcome.

Thus new insights into mechanisms leading to chronic hepatitis E and innovative antiviral treatment options are still needed.

Extrahepatic manifestation of HEV infection has been reported most commonly of the nervous system and the kidney while, e.g., Guillain-Barre syndrome, neuralgic amyotrophy, glomerulonephritis, meningitis, encephalitis, or myopathy could be associated with hepatitis E.

However, underlying mechanisms of the different manifestation and clinical outcome of extrahepatic HEV infection are still underreported but is of high interest.

Although HEV replication is thought to be controlled by the host immune system, viral factors (genotypes and mutants, virus diversity, virus evolution) can modulate HEV replication, infection and pathogenesis.

Limited knowledge exists on the contribution of virus-host interaction and HEV genome variants towards pathogenesis, immunological response, replication control and susceptibility to antiviral drugs; however, this limitation has to be reduced incrementally.  

In this Special Issue, we will summarize the current knowledge answering the many open questions albeit in part on HEV infection in terms of virological, immunological, one health (zoonosis) and global health level, in order to improve our knowledge on HEV pathogenesis, immunology, epidemiology and factors that influence HEV replication, chronification and risk assessment in humans and animals.

We thus invite submission of research and review manuscripts that cover any aspect of the pathogenesis, immunology, epidemiology, diagnosis, treatment and prevention of hepatitis E. I look very forward to your contributions which will give without any doubt a valuable and high ranking edition that will promote further developments in the exciting field of hepatitis E.

Thank you for your collaboration.

Prof. Dr. C. Thomas Bock
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Virology
    • HEV Virology & Pathogenicity
    • Immunology
  • One Health - HEV in Animals
    • HEV Zoonosis & Transmission
    • HEV Food and Blood product Safety
    • Prevention & Therapy
  • Global Health - HEV Epidemiology & Natural History
    • HEV Diversity
    • HEV Diagnostics
    • Clinical outcome & Chronic HEV
    • Risk Assessment & Gender Specificity
    • Extrahepatic Manifestation

Published Papers (6 papers)

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Research

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Open AccessArticle
Hepatitis E Virus Seroprevalence and Associated Risk Factors in Apparently Healthy Individuals from Osun State, Nigeria
Pathogens 2020, 9(5), 392; https://doi.org/10.3390/pathogens9050392 - 20 May 2020
Abstract
Hepatitis E virus (HEV) infection is a major public health concern in low-income countries, yet incidence and prevalence estimates are often lacking. Serum (n = 653) and faecal (n = 150) samples were collected from apparently healthy individuals using convenience sampling [...] Read more.
Hepatitis E virus (HEV) infection is a major public health concern in low-income countries, yet incidence and prevalence estimates are often lacking. Serum (n = 653) and faecal (n = 150) samples were collected from apparently healthy individuals using convenience sampling technique in six communities (Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo) from Osun State, Nigeria. Serum samples were analysed for total anti-HEV IgG/IgM and anti-HEV IgM using commercially available HEV ELISA kits. Total anti-HEV positive serum and all stool samples were analysed for HEV RNA by RT-PCR. Overall, 15.0% (n = 98/653) and 3.8% (n = 25/653) of the serum samples were positive for anti-HEV total and IgM antibodies, respectively. Total anti-HEV and IgM in Ore, Oke-Osun, Osogbo, Ede, Esa-Odo, and Iperindo was 21.0% (n = 13/62) and 3.2% (n = 2/62), 19.4% (n = 20/103) and 6.8% (n = 7/103), 11.4% (n = 12/105) and 2.9% (n = 3/105), 8.0% (n = 16/199) and 1.5% (n = 3/199), 22.0% (n = 22/100) and 10.0% (n = 10/100), and 17.9% (n = 15/84) and 0.0% (n = 0/84), respectively. All samples (stool and serum) were HEV RNA negative. Anti-HEV seroprevalence was associated with rural location, increasing age, alcohol consumption, and rearing of animals. This study demonstrated a high anti-HEV seroprevalence in Osun State, indicating the need to implement surveillance and asses the hepatitis E burden in Nigeria. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Open AccessArticle
Establishment of a Plasmid-Based Reverse Genetics System for the Cell Culture-Adapted Hepatitis E Virus Genotype 3c Strain 47832c
Pathogens 2020, 9(3), 157; https://doi.org/10.3390/pathogens9030157 - 25 Feb 2020
Abstract
The hepatitis E virus (HEV) causes acute and chronic hepatitis in humans. Investigation of HEV replication is hampered by the lack of broadly applicable, efficient cell culture systems and tools for site-directed mutagenesis of HEV. The cell culture-adapted genotype 3c strain 47832c, which [...] Read more.
The hepatitis E virus (HEV) causes acute and chronic hepatitis in humans. Investigation of HEV replication is hampered by the lack of broadly applicable, efficient cell culture systems and tools for site-directed mutagenesis of HEV. The cell culture-adapted genotype 3c strain 47832c, which represents a typical genotype predominantly detected in Europe, has previously been used for several basic and applied research studies. Here, a plasmid-based reverse genetics system was developed for this strain, which efficiently rescued the infectious virus without the need for in vitro RNA transcription. The cotransfection of T7 RNA polymerase-expressing BSR/T7 cells with one plasmid encoding the full-length viral genome and two helper plasmids encoding vaccinia virus capping enzymes resulted in the production of infectious HEV, which could be serially passaged on A549/D3 cells. The parental and recombinant virus exhibited similar replication kinetics. A single point mutation creating an additional restriction enzyme site could be successfully introduced into the virus genome of progeny virus, indicating that the system is suitable for site-directed mutagenesis. This system is the first plasmid-based HEV reverse genetics system, as well as the first reverse genetics system for HEV genotype 3c, and should therefore be of broad use for basic and applied HEV research. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Open AccessArticle
Comprehensive Evaluation of Hepatitis E Serology and Molecular Testing in a Large Cohort
Pathogens 2020, 9(2), 137; https://doi.org/10.3390/pathogens9020137 - 19 Feb 2020
Abstract
Introduction: Reliable and cost-effective diagnostics for hepatitis E virus (HEV) infection are necessary. The aim of our study was to investigate which diagnostic test is most accurate to detect HEV infection in immunocompetent and immunosuppressed patients in a real world setting. Patients and [...] Read more.
Introduction: Reliable and cost-effective diagnostics for hepatitis E virus (HEV) infection are necessary. The aim of our study was to investigate which diagnostic test is most accurate to detect HEV infection in immunocompetent and immunosuppressed patients in a real world setting. Patients and Methods: We performed a retrospective analysis of 1165 patients tested for HEV antibodies and HEV PCR at the same time point. Clinical, laboratory and virological data were taken from patient charts. HEV IgA was measured in a subgroup of 185 patients. Results: HEV RNA was detectable in 61 patients (5.2%); most of them (n = 49, 80.3%/n = 43, 70.5%) were HEV IgM+ and IgG+; however, 12 patients (19.6%) were HEV RNA positive/HEV IgM negative and 17 patients (27.8%) were HEV RNA positive/HEV IgG negative. Ten HEV RNA positive patients (16.4%) had neither HEV IgG nor IgM antibodies. Importantly, all of them were immunosuppressed. HEV IgA testing was less sensitive than HEV IgM for HEV diagnosis. Conclusions: HEV infection can be overlooked in patients without HEV specific antibodies. Performing PCR is necessary to diagnose or exclude HEV infection in immunocompromised hosts. In immunocompetent patients, a screening based on HEV antibodies (IgG/IgM) is sufficient. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Open AccessArticle
Hepatitis E Virus Shows More Genomic Alterations in Cell Culture than In Vivo
Pathogens 2019, 8(4), 255; https://doi.org/10.3390/pathogens8040255 - 22 Nov 2019
Abstract
Hepatitis E Virus (HEV) mutations following ribavirin treatment have been associated with treatment non-response and viral persistence, but spontaneous occurring genomic variations have been less well characterized. We here set out to study the HEV genome composition in 2 patient sample types and [...] Read more.
Hepatitis E Virus (HEV) mutations following ribavirin treatment have been associated with treatment non-response and viral persistence, but spontaneous occurring genomic variations have been less well characterized. We here set out to study the HEV genome composition in 2 patient sample types and 2 infection models. Near full HEV genome Sanger sequences of serum- and feces-derived HEV from two chronic HEV genotype 3 (gt3) patients were obtained. In addition, viruses were sequenced after in vitro or in vivo expansion on A549 cells or a humanized mouse model, respectively. We show that HEV acquired 19 nucleotide mutations, of which 7 nonsynonymous amino acids changes located in Open Reading Frame 1 (ORF1), ORF2, and ORF3 coding regions, after prolonged in vitro culture. In vivo passage resulted in selection of 8 nucleotide mutations with 2 altered amino acids in the X domain and Poly-proline region of ORF1. Intra-patient comparison of feces- and serum-derived HEV gt3 of two patients showed 7 and 2 nucleotide mutations with 2 and 0 amino acid changes, respectively. Overall, the number of genomic alterations was up to 1.25× per 1000 nucleotides or amino acids in in vivo samples, and up to 2.84× after in vitro expansion of the same clinical HEV strain. In vitro replication of a clinical HEV strain is therefore associated with more mutations, compared to the minor HEV genomic alterations seen after passage of the same strain in an immune deficient humanized mouse; as well as in feces and blood of 2 immunosuppressed chronically infected HEV patients. These data suggest that HEV infected humanized mice more closely reflect the HEV biology seen in solid organ transplant recipients. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Review

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Open AccessReview
Orthohepevirus C: An Expanding Species of Emerging Hepatitis E Virus Variants
Pathogens 2020, 9(3), 154; https://doi.org/10.3390/pathogens9030154 - 25 Feb 2020
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has received an increasing amount of attention from virologists, clinicians, veterinarians, and epidemiologists over the past decade. The host range and animal reservoirs of HEV are rapidly expanding and a plethora of emerging [...] Read more.
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has received an increasing amount of attention from virologists, clinicians, veterinarians, and epidemiologists over the past decade. The host range and animal reservoirs of HEV are rapidly expanding and a plethora of emerging HEV variants have been recently identified, some of which have the potential for interspecies infection. In this review, the detection of genetically diverse HEV variants, classified into and presumably associated with the species Orthohepevirus C, currently comprising HEV genotypes C1 and C2, by either serological or molecular approach is summarized. The distribution, genomic variability, and evolution of Orthohepevirus C are analyzed. Moreover, the potential risk of cross-species infection and zoonotic transmission of Orthohepevirus C are discussed. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Other

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Open AccessCase Report
Chronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment
Pathogens 2019, 8(3), 129; https://doi.org/10.3390/pathogens8030129 - 22 Aug 2019
Cited by 2
Abstract
Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, [...] Read more.
Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in vivo, we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle in vitro. First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect. Full article
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Dr. Richie Madden

HEV extrahepatic manifestations

 

Dr. Ansgar W. Lohse, Dr. Sven Pischke

Autoimmune markers, including cryoglobulinemia, in HEV infected patients

 

Dr. Anna Rosa Garbuglia

Clinical features of acute hepatitis E and their correlation with 3HEV  subtypes in Italy

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