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The cellular stress response is characterized by the production of heat shock proteins (HSP) that mediate cell recovery from and protection against potentially lethal injury. My laboratory is focused upon the role of HSPs in modulating virus-mediated disease in the central nervous system (i.e., neurovirulence). We have shown that the predominant inducible 70kDa HSP (hsp70) in neurons protects against viral neurovirulence in mouse models, despite the stimulatory effect of hsp70 on virus gene expression. The viral systems studied include: canine distemper virus (CDV), a ubiquitous and frequently fatal pathogen of dogs, raccoons, and numerous other animal species; measles virus (MeV), a human pathogen closely related to CDV; Vesicular Stomatitis Virus (VSV), a rhabdovirus that is highly neurotropic in mouse models. Studies from both animal models and cell culture have elucidated a basis for this protective effect. Virus infection of neurons stimulates a secretory release of hsp70, and the greater the levels of hsp70 within the virus-infected cell, the greater the level of extracellular release. Extracellular hsp70 activates uninfected macrophages through Toll-like receptors 2 and 4, activating antigen presentation functions and stimulating robust induction of type 1 interferon that in turn supports an enhanced adaptive immune response and viral clearance. Hsp70, released from the cell, thus serves as a damage-associated molecular pattern (DAMP) that signals the presence of virus infection to the immune system. This relationship supports a protective role of fever, a potent physiological stimulus for hsp70 induction that is a common accompaniment of microbial infections.
- Define the mechanism(s) of virus-induced hsp70 secretion from viable cells, with particular emphasis on exosomal release.
- Define the broader relevance of neuronal hsp70 release to protection against other neurotropic viruses.
- Define the broader relevance of hsp70 to enhanced innate and adaptive immune responses to viruses affecting other organ systems, with emphasis on the respiratory and gastrointestinal tracts.
- Define the broader role of extracellular hsp70 in mediating central nervous system inflammation in non-infectious diseases (e.g., immune mediated).