Studying the entry mechanism of non-enveloped and quasi-enveloped hepatitis E virus and the role of integrin β1

• Applicant: Dr. Viet Loan Dao Thi, Ph.D.
• Subject Area: Virology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467724337

Hepatitis E virus (HEV) is a major cause of acute fulminant hepatitis. Previously underestimated, HEV has not been well studied and many aspects of its life cycle remain poorly understood. In vitro, HEV infects a broad range of cell types, including liver, colon, lung, placenta, and brain cells. In vivo, extrahepatic manifestations in chronic HEV patients suggest extrahepatic sites of HEV replication. In order to fully understand the pathogenesis as well as broad tissue and species tropism of HEV, it is important to study the entry mechanism and identify its host entry factors. However, very few studies have been done on the mechanism of HEV entry in general.HEV is a non-enveloped virus (nHEV) but gains a membranous envelope from the host cell when budding from cells. This form of the virus is called quasi-enveloped HEV (eHEV). While nHEV is ingested and shed into feces for fecal-oral transmission to another host, eHEV is found circulating in the blood of infected patients. In this proposal, we aim to decipher the entry pathway(s) exploited by both eHEV and nHEV to enter host cells and study host factor(s) that mediate cell entry. We have established groundwork showing that integrin β1 (ITGB1), a transmembrane protein, is important for HEV entry, and that HEV entry likely involves endocytosis. In addition, we have data suggesting that HEV capsid mediates superinfection exclusion of new HEV particles, potentially through ITGB1 receptor mimicry. Our aims for this proposal are:1) Studying the role of ITGB1 in HEV entry. We will confirm and study the role of ITGB1 in HEV entry as well as identify its α integrin partner that co-mediates entry. 2) Deciphering the mechanism of ITGB1-mediated HEV entry. Here, we will investigate the pathways that HEV utilizes for entry, downstream of integrin activation. 3) Investigating the superinfection exclusion mechanism mediated by HEV capsid. In this aim, we will further confirm and study the role of the virus capsid, and specifically, the ITGB1 motif found on the capsid, in mediating superinfection exclusion of HEV.

• DFG Programme: Research Grants