Heat shock protein modulation of paramyxoviral disease

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DESCRIPTION (provided by applicant): Cellular heat shock proteins (HSPs) are produced at high levels following physiological stimuli such as fever. When released into the extracellular environment, HSPs stimulate proinflammatory cytokine responses, activate antigen presenting cells, and mediate cross-presentation of antigen. HSPs also stimulate gene expression of multiple virus families, causing increased viral cytopathic effect. The outcome of these seemingly diametrically opposed effects of HSP on viral virulence (i.e., promoting immune responses on one hand, and promoting viral replication on the other) has not been established for any viral system. It is our hypothesis that induction of HSP is host protective within an immune competent host, where direct immunostimulatory effects of HSP and/or HSP-mediated increases in viral antigenic burden facilitate adaptive antiviral immune responses that lead to viral clearance. The current Exploratory/Developmental Research Grant proposal will test this hypothesis using pharmacological induction of HSP (i.e., GGA treatment) to modify the outcome of measles virus (MV) airway infection in the cotton rat, testing the impact upon immune responses to wild type and vaccine MV strains. The virological and immunological responses of the cotton rat to airway challenge by wild type and vaccine MV are well-established. The HSP-responsiveness of MV is also well defined, so that differences in infection outcome between viruses that possess or lack a transcriptional response to HSP can be used to determine the degree to which HSP-dependent increases in viral gene expression determine immune sequela. Results will serve as the foundation for future studies that will include identification of immunological mechanisms underlying effects of GGA treatment and establishing the more broad relevance of our findings to related viral systems (e.g., human respiratory syncytial virus, an agent whose replication and host immune response can also be modeled in the cotton rat). PUBLIC HEALTH RELEVANCE: Fever is a consistent response to infection by numerous viral agents, yet it is unclear to what degree fever-induced proteins such as HSP are beneficial or detrimental to the host. Our work will identify the ability of an HSP-inducing drug (GGA) to promote clearance of a pathogenic MV isolate, establishing the potential of HSP induction to serve as a novel antiviral strategy.