Research Summary

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 (HSP72) stimulates gene expression of paramyxoviruses 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 (MV), a human pathogen closely related to CDV. Specifically, it has been shown that HSP72 forms complexes with the CDV and MV 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/HSP interaction. The HSP-mediated increase in viral gene expression in cell culture results in increased viral protein production, cytopathic effect, and release of infectious viral progeny. Cellular support of viral gene expression is a determinant of virulence, suggesting that HSP72 can serve as a determinant of the outcome of virus infection within an animal host.

Current research focuses upon identifying the mechanistic basis for HSP72-dependent increases in MV gene expression and the biological significance of virus-HSP72 interaction in brain. Our in vivo data support a model in which this virus-host interaction can have disparate outcomes depending upon host immune status. In an animal capable of mounting an effective cell mediated immune response, HSP72-dependent increases in viral gene expression facilitate clearance from brain by overcoming the host restricted low-levels of viral gene expression that otherwise result in persistence. This outcome is consistent with a host protective role for fever, a potent inducer of HSP72 in neurons. This outcome also suggests that viral variants which are less responsive to elevations in HSP72 will be better able to avoid this host protective response. Conversely, in an immune deficient animal, T cell responses are not adequate to contain the HSP72-dependent burst in viral replication and the result is enhanced neurovirulence.

Future goals are to establish the more broad relevance of virus-HSP72 interaction, examining the impact of MV-HSP72 interaction in non-neural tissues, and determining the degree to which HSP72 influences gene expression of other viral pathogens using similar mechanisms of regulated gene expression. Therapeutic implications of this line of investigation are that viral virulence can be controlled by manipulating cellular levels of HSP72.