Integrin α3 is involved in non-enveloped hepatitis E virus infection

Hepatitis E virus (HEV) causes acute and fulminant hepatitis worldwide. Although enveloped (e) and non -enveloped (ne) forms of HEV have been discovered, host factors involved in infection, including receptors, remain to be elucidated. Here, we identified integrin alpha 3 (encoded by ITGA3), a protein that binds and responds to the extracellular matrix, as an essential host factor for HEV infection. Integrin alpha 3 expression was lower in four HEV-non-permissive cell subclones than in an HEV-permissive subclone. ITGA3 knockout cells lost HEV permissibility, suggesting that integrin alpha 3 is critical for HEV infection. Stable expression of integrin alpha 3 in an HEV-non-permissive subclone provided permissibility only to infection by neHEV; expression of integrin alpha 3 lacking the ectodomain did not. Direct interaction between neHEV and the integrin alpha 3 ectodomain was confirmed by co-precipitation using a soluble integrin alpha 3-Fc. These results strongly suggest that integrin alpha 3 is a key molecule for cellular attachment and entry of neHEV.