Hepatitis E virus: host tropism and zoonotic infection

Novel genotypes of hepatitis E virus (HEV), i.e., HEV-5, HEV-7, and HEV-8, have been identified in wild boar, dromedary camels, and Bactrian camels, respectively, and they transmit to cynomolgus monkeys in a trans-species manner, raising the potential for zoonotic infection. Rabbits are the natural reservoir for rabbit HEV, but they are also susceptible to HEV-3 and HEV-4. It has been unknown whether rabbits are susceptible to HEV-5, HEV-7, and HEV-8. To investigate the infectivity of novel HEVs in rabbits and to assess whether rabbits are appropriate animal models for these HEVs, we inoculated Japanese white rabbits with HEV-5, HEV-7, and HEV-8, respectively. We observed that viral RNA was present in the fecal specimens of the HEV-8-inoculated rabbits and anti-HEV IgG antibodies were present in its sera, although anti-HEV IgM was undetectable and no significant elevation of ALT was observed. These results indicated that HEV-8 crossed species and infected the rabbits. No evidence for replication was observed in HEV-5 and HEV-7, suggesting that rabbits are not susceptible to these genotypes. The antibodies elicited in the HEV-8-infected rabbits did not protect them from the rabbit HEV challenge, suggesting that the antigenicity differs between HEV-8 and rabbit HEV. Antigenic analyses demonstrated that anti-HEV-8 antibodies reacted more strongly with homologous HEV-8 virus-like particles (VLPs) compared to heterologous rabbit HEV VLPs, but anti-rabbit HEV antibody had similar reactivity to the VLPs of rabbit HEV and HEV-8, suggesting that HEV-8 lacks some epitope(s) that exist in rabbit HEV and induced the neutralizing antibodies against rabbit HEV.

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Genotype 5 Hepatitis E Virus Produced by a Reverse Genetics System Has the Potential for Zoonotic Infection

Hepatology Communications ◽

10.1002/hep4.1288 ◽

2018 ◽

Vol 3 (1) ◽

pp. 160-172 ◽

Cited By ~ 21

Author(s):

Tian-Cheng Li ◽

Huimin Bai ◽

Sayaka Yoshizaki ◽

Yasushi Ami ◽

Yuriko Suzaki ◽

...

Keyword(s):

Hepatitis E Virus ◽

Reverse Genetics ◽

Hepatitis E ◽

Zoonotic Infection ◽

Genotype 5

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Production of infectious dromedary camel hepatitis E virus by a reverse genetic system: Potential for zoonotic infection

Journal of Hepatology ◽

10.1016/j.jhep.2016.07.013 ◽

2016 ◽

Vol 65 (6) ◽

pp. 1104-1111 ◽

Cited By ~ 28

Author(s):

Tian-Cheng Li ◽

Xianfeng Zhou ◽

Sayaka Yoshizaki ◽

Yasushi Ami ◽

Yuriko Suzaki ◽

...

Keyword(s):

Hepatitis E Virus ◽

Genetic System ◽

Hepatitis E ◽

Reverse Genetic System ◽

Dromedary Camel ◽

Reverse Genetic ◽

Zoonotic Infection

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Mechanism of Cross-Species Transmission, Adaptive Evolution and Pathogenesis of Hepatitis E Virus

Viruses ◽

10.3390/v13050909 ◽

2021 ◽

Vol 13 (5) ◽

pp. 909

Author(s):

Putu Prathiwi Primadharsini ◽

Shigeo Nagashima ◽

Hiroaki Okamoto

Keyword(s):

Adaptive Evolution ◽

Hepatitis E Virus ◽

Current Knowledge ◽

Hepatitis E ◽

Oral Route ◽

Open Reading Frames ◽

Industrialized Countries ◽

Zoonotic Infection ◽

Host Determinants ◽

Viral Determinants

Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. While the transmission in developing countries is dominated by fecal-oral route via drinking contaminated water, the zoonotic transmission is the major route of HEV infection in industrialized countries. The discovery of new HEV strains in a growing number of animal species poses a risk to zoonotic infection. However, the exact mechanism and the determinant factors of zoonotic infection are not completely understood. This review will discuss the current knowledge on the mechanism of cross-species transmission of HEV infection, including viral determinants, such as the open reading frames (ORFs), codon usage and adaptive evolution, as well as host determinants, such as host cellular factors and the host immune status, which possibly play pivotal roles during this event. The pathogenesis of hepatitis E infection will be briefly discussed, including the special forms of this disease, including extrahepatic manifestations, chronic infection, and fulminant hepatitis in pregnant women.

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Generation of a Bactrian camel hepatitis E virus by a reverse genetics system

Journal of General Virology ◽

10.1099/jgv.0.001618 ◽

2021 ◽

Vol 102 (7) ◽

Author(s):

Wenjing Zhang ◽

Yasushi Ami ◽

Yuriko Suzaki ◽

Yen Hai Doan ◽

Naokazu Takeda ◽

...

Keyword(s):

Cell Culture ◽

Culture System ◽

Hepatitis E Virus ◽

Reverse Genetics ◽

Hepatitis E ◽

Bactrian Camel ◽

Cell Culture System ◽

Zoonotic Infection ◽

Cynomolgus Monkeys ◽

A Cell

Bactrian camel hepatitis E virus (HEV) is a novel HEV belonging to genotype 8 (HEV-8) in the Orthohepevirus A species of the genus Hepevirus in the family Hepeviridae. HEV-8 cross-transmits to cynomolgus monkeys and has a potential risk for zoonotic infection. Until now, neither a cell-culture system to grow the virus nor a reverse genetics system to generate the virus has been developed. To generate replication-competent HEV-8 and to establish a cell-culture system, we synthesized capped genomic HEV-8 RNAs by in vitro transcription and used them to transfect into PLC/PRF/5 cells. A HEV-8 strain, HEV-8M2, was recovered from the capped HEV-8 RNA–transfected cell-culture supernatants and subsequently passaged in the cells, demonstrating that PLC/PRF/5 cells were capable of supporting the replication of the HEV-8, and that a cell-culture system for HEV-8 was successfully established. In addition to PLC/PRF/5 cells, A549 and Caco-2 cells appeared to be competent for the replication, but HepG2 C3/A, Vero, Hela S3, HEp-2C, 293T and GL37 cells were incompetent. The HEV-8M2 strain was capable of infecting cynomolgus monkeys by an intravenous inoculation, indicating that HEV-8 was infectious and again carried a risk for zoonotic infection. In contrast, HEV-8 did not infect nude rats and BALB/c nude mice, suggesting that the reservoir of HEV-8 was limited. In addition, the replication of the HEV-8M2 strain was efficiently abrogated by ribavirin but not by favipiravir, suggesting that ribavirin is a drug candidate for therapeutic treatment of HEV-8-induced hepatitis. The infectious HEV-8 produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of type E hepatitis.

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Review of Hepatitis E Virus in Rats: Evident Risk of Species Orthohepevirus C to Human Zoonotic Infection and Disease

Viruses ◽

10.3390/v12101148 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1148

Author(s):

Gábor Reuter ◽

Ákos Boros ◽

Péter Pankovics

Keyword(s):

Hepatitis E Virus ◽

Current Knowledge ◽

Laboratory Diagnosis ◽

Hepatitis E ◽

Clinical Aspects ◽

Special Focus ◽

Human Pathogens ◽

Extrahepatic Manifestations ◽

Zoonotic Infection ◽

Symptomatic Disease

Hepatitis E virus (HEV) (family Hepeviridae) is one of the most common human pathogens, causing acute hepatitis and an increasingly recognized etiological agent in chronic hepatitis and extrahepatic manifestations. Recent studies reported that not only are the classical members of the species Orthohepevirus A (HEV-A) pathogenic to humans but a genetically highly divergent rat origin hepevirus (HEV-C1) in species Orthohepevirus C (HEV-C) is also able to cause zoonotic infection and symptomatic disease (hepatitis) in humans. This review summarizes the current knowledge of hepeviruses in rodents with special focus of rat origin HEV-C1. Cross-species transmission and genetic diversity of HEV-C1 and confirmation of HEV-C1 infections and symptomatic disease in humans re-opened the long-lasting and full of surprises story of HEV in human. This novel knowledge has a consequence to the epidemiology, clinical aspects, laboratory diagnosis, and prevention of HEV infection in humans.

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The Hepatitis E Virus Open Reading Frame 2 Protein: Beyond Viral Capsid

Frontiers in Microbiology ◽

10.3389/fmicb.2021.739124 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhaobin Zhou ◽

Yinqian Xie ◽

Chunyan Wu ◽

Yuchen Nan

Keyword(s):

Hepatitis E Virus ◽

Hepatitis E ◽

Open Reading Frames ◽

Viral Capsid ◽

Reading Frame ◽

Host Tropism ◽

Orf2 Protein ◽

Acute Hepatitis E ◽

Open Reading Frame 2 ◽

Reading Frames

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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