Type III interferons are expressed by C oxsackievirus‐infected human primary hepatocytes and regulate hepatocyte permissiveness to infection

Summary Hepatitis is a common and potentially fatal manifestation of severe C oxsackievirus infections, particularly in newborn children. Little is known of the immune‐mediated mechanisms regulating permissiveness to liver infection. It is well established that type I interferons ( IFNs ) play an important role in the host innate immune response to C oxsackievirus infections. Recent studies have highlighted a role for another IFN family, the type III IFNs (also called IFN‐ λ), in anti‐viral defence. Whether type III IFNs are produced by hepatocytes during a C oxsackievirus infection remains unknown. Moreover, whether or not type III IFNs protects hepatocytes from a C oxsackievirus infection has not been addressed. In this study, we show that primary human hepatocytes respond to a C oxsackievirus B 3 ( CVB 3) infection by up‐regulating the expression of type III IFNs . We also demonstrate that type III IFNs induce an anti‐viral state in hepatocytes characterized by the up‐regulated expression of IFN‐stimulated genes, including IFN‐stimulated gene (ISG15), 2′‐5′‐oligoadenylate synthetase 2 (OAS2), protein kinase regulated by dsRNA (PKR) and myxovirus resistance protein 1 (Mx1). Furthermore, our study reveals that type III IFNs attenuate CVB 3 replication both in hepatocyte cell lines and primary human hepatocytes. Our studies suggest that human hepatocytes express type III IFNs in response to a C oxsackievirus infection and highlight a novel role for type III IFNs in regulating hepatocyte permissiveness to this clinically relevant type of virus.