Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections are common causes of epidemic food-borne and water-borne hepatitis in under-developed regions of the world. Recently sporadic HEV infections have emerged as a significant public health hazard in well-developed countries. The recognition of zoonotic and blood-borne HEV transmission and its ability to persistent in immunosuppressed individuals is also alarming. Approximately 20% of the U.S. population is seropositive for HEV, indicating that HEV exposure is more common than previously thought. Although both recognized as non-enveloped viruses, recent studies show that HAV and HEV circulate in the blood as quasi-enveloped particles. These novel particles differ from classic enveloped viruses in that no viral antigens are present on the surface of their membrane, therefore are highly resistant to neutralizing antibodies. The impact of this quasi-envelopment on hepatitis virus life cycle, immunity, and pathogenesis is poorly understood. This proposal will explore the mechanisms by which quasi- enveloped HAV and HEV enter the cells and are neutralized by antibodies.
Aim 1 will test the hypothesis that entry of quasi-enveloped HAV and HEV is through a cellular mechanism for extracellular vesicular uptake.
Aim 2 will determine the mechanism of neutralization for quasi-enveloped HAV and HEV. Completion of these aims will address several of the most significant gaps in our understanding of the quasi-enveloped virus life cycle and pathogenesis.

Public Health Relevance

Hepatitis A virus (HAV) and hepatitis E virus (HEV) are a common cause for enterically transmitted hepatitis in developing countries. Hepatitis E is also an emerging disease in well-developed countries. Although known as non-enveloped viruses for decades, recent studies show both viruses circulate in the blood as 'quasi- enveloped' particles. This led us to rethink the life cycle of these viruses and the pathogenesis associated with these infections. In this project, we will explore the mechanisms by how 'quasi-enveloped' HAV and HEV enter cells and are neutralized by antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI122228-02
Application #
9201304
Study Section
Virology - B Study Section (VIRB)
Program Officer
Koshy, Rajen
Project Start
2016-01-06
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Feng, Zongdi (2016) Causation by HEV of extrahepatic manifestations remains unproven. Liver Int 36:477-9
Yin, Xin; Ambardekar, Charuta; Lu, Yurong et al. (2016) Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses. J Virol 90:4232-42
Yin, Xin; Li, Xinlei; Feng, Zongdi (2016) Role of Envelopment in the HEV Life Cycle. Viruses 8: