Hepatitis E virus (HEV) is an important but extremely understudied pathogen. Genotypes 1 and 2 are restricted to humans, whereas genotypes 3 and 4 infect humans and other animals. The long-term goals of this project are to delineate the mechanisms of HEV cross-species infection and identify host and viral determinants of host range and pathogenesis.
In specific aim 1, we hypothesize that the hypervariable region (HVR) in ORF1 and the inserted host gene sequences in HVR determine HEV host range. Our preliminary studies suggested that HVR and its adjacent region are involved in HEV tropism. The recent findings that host S17 and S19 gene sequences were inserted into the HVR of HEV that resulted in recombinant viruses with expanded cell tropism of different animal origins lends further credence to our hypothesis. We will determine (a) if a genotype 1 human HEV (infecting humans only) will acquire the ability to infect pigs and rabbits if its HVR is replaced with that o a zoonotic genotype 3 HEV, (b) if the genotype 1 human HEV with an inserted host S17 sequence in the HVR will acquire the ability to infect pigs and rabbits, and (c) if the adjacent X domain in ORF1 plays a role, together with HVR, in determining the host range.
In specific aim 2, we hypothesize that the genotype- specific HVR sequences and/or inserted host sequences contribute to HEV pathogenicity. Increased pathogenicity by recombination events between host gene sequence and virus genomes has been reported for other viruses. The fact that the neurological and chronic cases of hepatitis E are all caused by the zoonotic genotype 3 HEV and that quasispecies compartmentalization in CSF and serum of clonal HEV sequences within the HVR region was identified from neurological cases suggested that the HVR plays a role in virus pathogenicity and emergence of neurotropic variants. We will determine (a) if the genotype 3 virus with the S17 insertion in HVR is more virulent than the virus without the insertion, (b) if the genotype 3 virus with a S17 insertion establishes chronic infection in pigs, and (c) if the HVR and its adjacent regions evolve during chronic HEV infection in pigs to produce neurotropic variants.
In specific aim 3, we hypothesize that interferon stimulated gene 15 (ISG15) plays a role in HEV infection and host anti-HEV response. Our preliminary studies showed that HEV replication requires an active ubiquitin-proteasome system and that overexpression of ISG15 inhibited HEV replication in a HEV replicon system. The findings that the papain-like cysteine protease (PCP) domain in HEV ORF1 has deubiquitinating activity and carries out deISGylation of ISG15-conjugated proteins support our hypothesis. By using an efficient HEV infection cell culture model with genotype 3 HEV Kernow C- 1 strain, we will determine (a) if overexpression of ISG15 will inhibit genotype 3 HEV infection, and if so, what is the mechanism of inhibition, (b) if HEV counteracts ISG15 production and ISGylation, and if so, if the PCP domain plays a role in antagonizing ISG15 function. By completing this project, we expect to identify the viral determinant(s) for HEV host range and pathogenicity and delineate the role of ISG15 in anti-HEV response.

Public Health Relevance

Hepatitis E virus (HEV) is an important but extremely understudied human pathogen causing significant public health problem in developing countries but is also endemic in the United States and other industrialized countries. In this project, we wil identify the genetic determinant(s) for HEV cross-species infection and host range, and delineate the role of interferon-stimulated gene 15 (ISG15) in HEV infection and host anti-HEV defense. The information from this project will be important for devising effective prevention and treatment strategies against HEV.

National Institute of Health (NIH)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Koshy, Rajen
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Virginia Polytechnic Institute and State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Yugo, Danielle M; Cossaboom, Caitlin M; Meng, Xiang-Jin (2014) Naturally occurring animal models of human hepatitis E virus infection. ILAR J 55:187-99
Yugo, Danielle M; Meng, Xiang-Jin (2013) Hepatitis E virus: foodborne, waterborne and zoonotic transmission. Int J Environ Res Public Health 10:4507-33
Cossaboom, Caitlin M; Cordoba, Laura; Sanford, Brenton J et al. (2012) Cross-species infection of pigs with a novel rabbit, but not rat, strain of hepatitis E virus isolated in the United States. J Gen Virol 93:1687-95
Kenney, Scott P; Pudupakam, R S; Huang, Yao-Wei et al. (2012) The PSAP motif within the ORF3 protein of an avian strain of the hepatitis E virus is not critical for viral infectivity in vivo but plays a role in virus release. J Virol 86:5637-46
Karpe, Yogesh A; Meng, Xiang-Jin (2012) Hepatitis E virus replication requires an active ubiquitin-proteasome system. J Virol 86:5948-52
Feagins, Alicia R; Cordoba, Laura; Sanford, Brent J et al. (2011) Intergenotypic chimeric hepatitis E viruses (HEVs) with the genotype 4 human HEV capsid gene in the backbone of genotype 3 swine HEV are infectious in pigs. Virus Res 156:141-6
Meng, Xiang-Jin (2011) From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 161:23-30
Pudupakam, R S; Kenney, Scott P; Cordoba, Laura et al. (2011) Mutational analysis of the hypervariable region of hepatitis e virus reveals its involvement in the efficiency of viral RNA replication. J Virol 85:10031-40
Cossaboom, Caitlin M; Cordoba, Laura; Dryman, Barbara A et al. (2011) Hepatitis E virus in rabbits, Virginia, USA. Emerg Infect Dis 17:2047-9
Kwon, Hyuk Moo; LeRoith, Tanya; Pudupakam, R S et al. (2011) Construction of an infectious cDNA clone of avian hepatitis E virus (avian HEV) recovered from a clinically healthy chicken in the United States and characterization of its pathogenicity in specific-pathogen-free chickens. Vet Microbiol 147:310-9

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