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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. While this protective role is well documented in metabolic, degenerative, and ischemic brain injury, focus upon the role of HSPs in the modulation of a virus’ ability to induce disease in nervous tissue (i.e., neurovirulence) is conspicuously lacking.
Research performed in my laboratory has shown that the predominant inducible 70kDa HSP (hsp70) stimulates gene expression of viruses having a predilection for growth in neurons. The primary viral systems studied include canine distemper virus (CDV), a ubiquitous and frequently fatal pathogen of dogs, raccoons, and numerous other animal species, and measles virus (MeV), a human pathogen closely related to CDV. Specifically, it has been shown that hsp70 forms complexes with the CDV and MeV core particle, the core particle being the repository of the virus' genetic information. Viral gene expression is increased as a result of this core-particle/hsp70 interaction. The hsp70-mediated increase in viral gene expression in cell culture results in increased viral protein production, cytopathic effect, and release of infectious viral progeny.
Current research focuses upon the biological significance of virus-hsp70 interaction in brain. Our data support a model in which this virus-host interaction can have disparate outcomes depending upon host immune status. The approach uses the mouse model of brain infection, where susceptibility is determined by H-2 haplotype. The H-2b haplotype is associated with inefficient adaptive immune responses to MeV challenge, resulting in enhanced viral neurovirulence. The H-2d haplotype is associated with a robust adaptive immune response to MeV and resistance to infection. Transgenic overexpression of hsp70 in neurons, the target of MeV replication, promotes neurovirulence in H-2b mice whereas it promotes clearance in H-2d mice. Both hsp70-dependent outcomes reflect a viral transcriptional response to the stress protein. The host protection observed in the H-2d mice is attributed to enhanced innate immune responses associated with Toll-like receptor (TLR) signaling. In particular, there is enhanced TLR-2 and TLR-4 activation in transgenic infected H-2d mice relative to non-transgenic infected mice. Results are consistent with extracellular release of hsp70 from virus infected cells, enhanced innate immune responses through TLR signaling. Such release (and thus signaling) would be enhanced for virus mounting a transcriptional response to hsp70 due to the increased virus-induced cytopathic effect.
These findings have several broad implications:
Current experimental aims: