Hepatitis E is an important public health disease with a high mortality rate of up to 28% in infected pregnant women. Recently, chronic HEV infection has become an emerging and significant clinical problem worldwide in immunocompromised individuals such as organ transplant recipients and patients with HIV, lymphoma and leukemia with considerable morbidity and mortality. Approximately 58-92% of the HEV-infected organ transplant recipients developed chronic HEV infection but the mechanism leading to the progression into chronicity remains unknown. The long-term goal of this project is to develop an animal model for chronic hepatitis E to study the mechanisms of HEV immunopathogenesis and intervention strategies.
In aim 1, we hypothesize that HEV infection in pigs under immunosuppressive conditions will mimic the course of chronic HEV infection in immunocompromised individuals, which will enable us to delineate the predictive immunological factors leading to the progression into chronicity. Pigs will be immunosuppressed to mimic the immunosuppressive conditions in organ transplant recipients and then experimentally infected with HEV. The immunological, pathological, biochemical, virological and clinical parameters of HEV infection and hepatitis will also be analyzed and compared to identify the broad predictive factors for progression into chronicity.
In aim 2, we hypothesize that impairment of T-cell responses, particularly CD4+ and CD8+ T-cell responses, is responsible for the progression into chronicity in immunocompromised individuals. We will determine if depletion of specific CD4+ or CD8+ T cell subsets in chickens will lead to chronic infection and severe hepatitis in chickens infected with avian HEV. Chickens depleted of either CD4 or CD8 T cells will be experimentally infected with avian HEV, and assessed for pathological, biochemical, virological, immunological and clinical parameters of hepatitis. Adoptive transfer CD4+ or CD8+ T cells into immune cell-depleted chickens will also be performed.
In aim 3, we hypothesize that the humoral immune response is a double-edged sword in that it is important in control of HEV infection but it also involves in immune-mediated hepatic damages. B cell- depleted chickens as well as immunoglobulin (Ig) heavy chain homozygous knockout (-/-) piglets and wild-type littermate (+/+) will be experimentally infected with HEV, hepatic lesions, immunological, biochemical and virological parameters of hepatitis will be assessed and compared. The Ig heavy chain(-/-) knockout piglets will also be passively transferred with a HEV-specific antiserum followed by HEV challenge. By completing this project, we anticipate that a unique animal model for chronic hepatitis E will be established, and that the predictive immunological factors leading to chronic infection will be identified, the T cell epitopes responding to HEV infection mapped, and the mechanisms of HEV immunopathogenesis and chronic infection delineated. The results will be important for devising effective prevention and treatment strategies against HEV.

Public Health Relevance

Hepatitis E is an important public health disease and chronic hepatitis E virus (HEV) infection has become an emerging and significant clinical problem worldwide in immunocompromised individuals with considerable morbidity and mortality. This project will develop a useful animal model for chronic hepatitis E to delineate the mechanisms of immunopathogenesis and identify the predictive immunological factors leading to progression into chronicity. The results will be very important for devising effective prevention and treatment strategies against HEV in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI050611-09
Application #
8525789
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2002-02-01
Project End
2017-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$395,425
Indirect Cost
$145,425
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
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
Owolodun, Olajide A; Gimenez-Lirola, Luis G; Gerber, Priscilla F et al. (2013) Development of a fluorescent microbead-based immunoassay for the detection of hepatitis E virus IgG antibodies in pigs and comparison to an enzyme-linked immunoassay. J Virol Methods 193:278-83
Meng, Xiang-Jin (2013) Zoonotic and foodborne transmission of hepatitis E virus. Semin Liver Dis 33:41-9
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

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