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. This protective role is well documented in metabolic, degenerative, and ischemic brain injury, but our group was the first to address how these same HSP influence a virus’ ability to spread and cause disease in the nervous system.
Research performed in my laboratory showed that the major inducible 70 kDa heat shock protein (hsp70) is induced by and supports intracellular replication of viruses belonging to diverse families, with specific focus on measles and canine distemper virus (paramyxoviruses) and vesicular stomatitis virus (a rhabdovirus). Paradoxically, this virus-hsp70 interaction is protective in mouse models of viral neurovirulence, enhancing T cell mediated immune clearance in an interferon β (IFN-β)-dependent manner. Protection reflects early release of hsp70 from viable infected neurons and induction of strong innate immune responses in uninfected brain macrophages, including the induction of IFN-β through Toll-like receptor 4. Potency of the response is inherent in the fact that hsp70 is released at a time when pathogen-associated molecular patterns (PAMPs) are in low abundance, and that the innate response is driven by uninfected cells, free from viral interference. Release of hsp70 from viable cells is primarily exosomal, and infection enhances total exosome release and hsp70 content on the surface of exosomes. Exosome content of hsp70 reflects levels of hsp70 in the infected cell. Findings have broad virological relevance and support a protective role for fever, a potent stimulus for hsp70 induction. While protective in the context of microbial infection, recent findings support potential untoward effects of inappropriate extracellular hsp70 release in non-infectious neuroinflammatory conditions.
- relevance of the hsp70-TLR4 immune axis to protection against other neurovirulent viruses
- mechanisms regulating extracellular release of hsp70 in virus infection
- the role of extracellular hsp70 in neuroinflammatory responses in both infectious and non-infectious diseases
- novel uses of hsp70 as a vaccine adjuvant for viral infections
Additional collaborative research support is provided in the general areas of neurovirology and neuropathology.