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A secreted viral non-structural protein determines intestinal norovirus pathogenesis and vaccination

ABSTRACT: Secreted non-structural protein 1 of norovirus counteracts IFN-l immunity and is a vaccine target.

PROVIDER: PRJEB27021 | ENA |

REPOSITORIES: ENA

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A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis.

Project description:Murine norovirus (MNoV) infects a low percentage of enteric tuft cells and can persist in these cells for months following acute infection. Both tuft-cell tropism and resistance to interferon-λ (IFN-λ)-mediated clearance during persistent infection requires the viral nonstructural protein 1/2 (NS1/2). We show that processing of NS1/2 yields NS1, an unconventionally secreted viral protein that is central for IFN-λ resistance. MNoV infection globally suppresses intestinal IFN-λ responses, which is attributable to secreted NS1. MNoV NS1 secretion is triggered by caspase-3 cleavage of NS1/2, and a secreted form of human NoV NS1 is also observed. NS1 secretion is essential for intestinal infection and resistance to IFN-λ in vivo. NS1 vaccination alone protects against MNoV challenge, despite the lack of induction of neutralizing anti-capsid antibodies previously shown to confer protection. Thus, despite infecting a low number of tuft cells, NS1 secretion allows MNoV to globally suppress IFN responses and promote persistence.

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Transcriptional analysis of murine norovirus infection of primary bone marrow-derived macrophages

Project description:Murine norovirus is genetically similar to human norovirus, and offers both an efficient in vitro cell culture system and animal model by which to investigate the molecular basis of replication. Here, we present a detailed global view of host alterations to cellular pathways that occur during the progression of a norovirus infection. This was accomplished for both RAW264.7 (RAW) cells, an immortalized cell line widely used in in vitro replication studies, and primary bone marrow-derived macrophages (BMDM), representing a permissive in vivo target cell in the host. Murine norovirus replicated in both cell types, although detected genome copies were approximately one log lower in BMDM compared to RAW cells. RAW and BMDM cells shared an IRF3/7-based IFN response that occurred early in infection. In RAW264.7 cells, transcriptional upregulation and INF-ß expression were not coupled, in that a significant delay in the detection of secreted INF-ß was observed. In contrast, primary BMDM showed an early upregulation of transcripts and immediate release of INF-ß that might account for lower virus yield. Differences in the transcriptional pathway responses included a marked decrease in expression of key genes in the cell cycle and lipid synthesis pathways in RAW264.7 cells compared to that of BMDM. Our comparative analysis indicates the existence of varying host responses to virus infection in populations of permissive cells. Awareness of these differences at the gene level will be important in the application of a given permissive cell culture system to the study of norovirus immunity, pathogenesis, and drug development.

2018-06-13 | GSE111642 | GEO

Gene expression profiling of human gastric tumour cells (HGT-1) harboring genotype I human norovirus replicons

Project description:Gene expression analysis of GI human norovirus (HuNoV) replicon in human gastric tumor cells (HGT-NV), IFN-cured population of replicon-harboring HGT-1 cells (HGT-Cured) and wild-type parental HGT-1 cells (HGT) to provide insight into the cellular factors promoting human norovirus replication in vitro.

2019-09-10 | GSE111041 | GEO

Tropism for tuft cells determines norovirus pathogenesis

Project description:Intestinal tuft cells are the physiologic target cell of murine norovirus and this tropism determines transkingdom interactions.

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