Regulators of the Cellular Response to Viruses

Kasat, Roli Mandhana

doi:https://doi.org/10.21985/n2-h2x7-ss61

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Regulators of the Cellular Response to Viruses

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The cellular innate immune response to viruses is a defense mechanism executed by most cells in the human body to form the initial barrier to virus replication. Detection of viral nucleic acids initiates widespread gene expression changes that combine to establish an antiviral state and stimulate professional immune cell activation. This system co-evolved with viruses that can mutate to develop new evasion and escape strategies, forcing the innate immune system to adapt and form novel antiviral mechanisms as well. A deeper understanding of the complex cellular response to viruses is needed to detect and treat established and emerging viral infections as well as immune and autoimmune disorders. This level of understanding requires not only studying the components of the cellular innate immune response but also studying the viral factors that enable evasion and antagonism of the system. Harnessing these cellular and viral features could improve the development of diagnostics, antiviral drugs, and therapeutics for immune and autoimmune diseases. The work presented in this thesis furthers the knowledge about both cellular and viral components related to the innate immune response. Virus- regulated gene expression changes assayed by RNA-sequencing revealed the presence of thousands of previously-unannotated RNAs as well as other previously unrecognized virus-regulated RNAs. These primarily noncoding RNAs are candidates for regulatory or direct antiviral function and could be potential targets in pharmaceutical development for antivirals. The use of viral inhibitors of the innate immune response in drug development is an under-explored area. A proof of this concept is demonstrated by experiments using a family of Paramyxovirus IFN evasion proteins to suppress excessive immune signaling due to laboratory-generated and patient-derived mutations that hyperactivate the RNA sensor, MDA5. The results presented in this thesis not only advance the current understanding of cellular innate immunity and elucidate the expanding roles of noncoding RNAs in antiviral responses, but also establish new directions for the development of diagnostics and therapeutics.

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