Author

Jayeeta Dhar

Date of Award

2016

Degree Type

Thesis

Degree Name

Doctor of Philosophy in Regulatory Biology

Department

Biology

Subject Headings

Biology, Molecular Biology, Virology

Abstract

Pneumonia Virus of Mice (PVM) and Respiratory Syncytial Virus (RSV) are negative sense, single-stranded, enveloped RNA viruses from Pneumovirus genus, Paramyxoviridae family. RSV is the leading cause of respiratory diseases in infants. PVM causes similar respiratory illness in mice. PVM is used as an animal model to study RSV pathogenesis because of its similarity with RSV infection. Viral infection induces type I interferon (IFN) response as an antiviral strategy. PVM and RSV both have two non-structural (NS) proteins that are known to be IFN antagonists. While RSV can target different signaling components of IFN pathway, the mechanism of IFN suppression for PVM was unknown. We have identified that PVM can also target different signaling components of IFN pathway to circumvent the host immune system. Our observations showed that PVM NS proteins facilitate proteasome-mediated degradation of RIG-I, IRF3, STAT2 in IFN pathway by direct interactions with them. Production of several Interferon Stimulated Genes (ISGs) is the distal part of the IFN pathway. We have identified that NS proteins of PVM can also target a few of them such as TRAFD1, IFITM1, ISG20, and IDO for complete suppression of the host immune system.

RSV NS proteins play a similar role to suppress IFN pathway by targeting TBK1, RIG-I, IRF3, IRF7, and STAT2. Our study has identified one ISG, OASL, that has antiviral properties against RSV and documented that to counteract this antiviral property of OASL, RSV NS proteins can degrade OASL in a proteasome-dependent way.

These above observations help us to delineate the complete suppression mechanism for the whole Pneumovirus genus, both for PVM and RSV by providing the first experimental evidence of signaling components from the IFN pathway targeted by PVM to suppress the IFN response. PVM is a clinically relevant animal model that will help us to find new therapeutic strategies against Pneumovirus infection. RSV study with one of those important ISGs, OASL, is also important to uncover the target substrates of the entire IFN pathway. Together these findings help us to delineate new immune modulatory strategies for the whole Pneumovirus genus.

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