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Modulation and roles of stress-responsive proteins in coxsackievirus infection

University of British Columbia

Viral myocarditis is an inflammatory heart disease caused by viral infection, which is a major cause of sudden death in children and young adults. Among the various viruses, coxsackievirus B3 (CVB3) is a predominant pathogen of viral myocarditis. As CVB3 replication is tightly tangled with signaling pathways in host cells, an in-depth study of CVB3-host interactions would promote the understanding of the pathogenesis of viral myocarditis and provide critical drug targets for the development of therapeutics. CVB3 infection induces different types of stress in host cells, and in turn, the cells respond to the stress via expressing certain stress-responsive proteins (SRPs) to counteract the stress for cell survival. During the co-evolution of virus and host, CVB3 has developed sophisticated strategies to modulate and utilize SRPs to benefit its own replication. The main objective of this dissertation is to investigate the modulation and functional roles of SRPs in CVB3 infection and CVB3-induced myocardium damage. I hypothesize that 1) CVB3 infection differentially regulates the expression and activity of SRPs at transcription, translation or post-translation level; 2) the dysregulation of SRPs benefits CVB3 replication and promotes CVB3-induced cell damage. This dissertation mainly focuses on two SRPs, the inducible heat shock 70 kDa protein (Hsp70) and nuclear factor of activated T-cell 5 (NFAT5), during CVB3 infection. Using in vitro (cell culture) and in vivo (mouse) models, I demonstrated an increase of Hsp70 but a decrease of NFAT5 during CVB3 infection. Further studies elucidated the mechanism underlying such changes as well as the feedback effects on CVB3 replication. Hsp70 was upregulated via CaMKII-HSF1 signaling cascade activated in CVB3 infection and in turn promoted CVB3 infectivity via stabilizing viral genome and benefiting viral translation. NFAT5 was cleaved by CVB3 proteases 2A and 3C, generating a 70 kDa dominant negative truncate, which inhibited the iNOS-mediated anti-viral activity of NFAT5. Together, my findings have uncovered the new roles of SRPs in CVB3 infection and potential novel drug targets for CVB3-induced myocarditis.

Text

2017-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62935

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/