Mouse Norovirus infection reduces the surface expression of MHC class I proteins and inhibits CD8+ T cell recognition and activation.

Human Noroviruses are highly infectious, single stranded RNA (ssRNA) viruses and the major cause of non-bacterial gastroenteritis worldwide. With the discovery of Murine Norovirus (MNV) and the introduction of an effective model for norovirus infection and replication, knowledge about infection mechanisms and its impact on the host immune response has progressed. A major player in the immune response against viral infections is the group of major histocompatibility complex (MHC) class I proteins, which present viral antigen to immune cells. We have observed that MNV interferes with the antigen presentation pathway in infected cells by reducing the surface expression of MHC class I proteins. We have shown that MNV infected dendritic cells or macrophages have a reduced surface expression of MHC class I proteins compared to uninfected and bystander cells. Transcriptional analysis revealed that this defect is not due to decreased amount of mRNA, but is reflected at the protein level. A defect we have identified to be mediated via the MNV NS3 protein. Significantly, treatment of MNV-infected cells with the endocytic recycling inhibitor Dynasore completely restored the surface expression of MHC class I, whereas treatment with the proteasome inhibitor MG132 partly restored the surface expression of MHC class I. These observations indicate a role of endocytic recycling and proteasome-mediated degradation of the protein. Importantly, we show that due to the reduced surface expression of MHC class I proteins, antigen presentation is inhibited, resulting in the inability of CD8+ T cells to become activated in the presence of MNV infected cells. IMPORTANCE Human Noroviruses (HuNoV) are the major cause of non-bacterial gastroenteritis worldwide and cause a great burden on patients and health systems every year. So far, no antiviral treatment or vaccine is available. We show that MNV evades the host immune response by reducing the amount of MHC class I proteins displayed on the cell surface. This reduction leads to a decrease in viral antigen presentation and interferes with the CD8+ T cell response. CD8+ T cells respond to foreign antigen by activating cytotoxic pathways and inducing immune memory to the infection. By evading this immune response MNV is able to replicate efficiently in the host and cells are impaired in their ability to respond to consecutive infections. These findings have a major impact on our understanding of how Noroviruses interact with the host immune response and manipulate immune memory.