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Title: Innate sensing and regulation during enteric caliciviruses infections
Author: Jahun, Aminu Suleiman
ISNI:       0000 0004 7968 5099
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Several decades after the discovery of the human norovirus, with thousands of lives and billions of dollars lost, the lack of a robust cell culture system still severely hampers development of vaccines and therapeutics. This is likely in large part as a result of our limited understanding of the immune responses against an infection with the virus. Here, the presence of a RIG-I/STING-dependent innate response pathway that restricts the replication of noroviruses is described, and an attempt by the murine norovirus to subvert it through expression of an accessory protein is demonstrated. We show that both RIG-I and STING are required for a robust interferon response to infection with MNV1 in primary BMDMs and RAW264.7 cells, with a significant increase in viral titres following infection in RIG-I- and STING-deficient cells. We also show that STING is non-canonically activated in MNV1-infected cells partly in a RIG-I dependent manner. Furthermore, our data indicate that the MNV VF1 protein binds to STING and can inhibit interferon induction downstream of RIG-I. Secondly, while exploring the mechanisms for the differential induction of interferon sub- types, we show that depletion of MED23 leads to a reduction in expression of both types I and III IFNs in human and mouse cell lines. We also show that Med23 knockout cells undergo genetic compensation, suggesting a critical role for MED23 in this pathway. Mechanistically, we show that MED23 interacts with IRF3, and is required for recruitment of RNA Polymerase II to promoters of IRF3-dependent genes. Taken together, our data indicate that MED23 plays a central role in antiviral responses by coupling IRF3 activation and RNA Pol II recruitment.
Supervisor: Goodfellow, Ian G. Sponsor: Nigerian Government
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: norovirus ; calicivirus ; gastroenteritis ; interferon response ; innate immunity ; MDA5 ; RLR ; immune evasion ; STING ; RIG-I ; MED23 ; IRF3 ; Genetic compensation ; Transcriptional adaptation ; MNV ; HuNoV ; IFN ; cGAS