General Research Interestvirus-heat shock protein interaction and the impact on neurovirulence
Research DescriptionCellular heat shock proteins (HSPs) are known for their support of viral gene expression, and for influencing innate and adaptive immune responses, yet nothing is known about how virus-HSP interaction may influence viral virulence. Our laboratory uses the mouse model of measles virus (MeV) neuronal infection in brain to establish the in vivo significance of this virus-host interaction. Using transgenic mice that selectively overexpress the major inducible 70 kDa HSP (hsp70) in neurons, we have shown that hsp70-dependent stimulation of MeV transcription causes enhanced neurovirulence in an immune compromised host, yet supports viral clearance in an immune competent host. Clearance requires the viral transcriptional response to hsp70, and is attributed to both increased innate and adaptive antiviral immune responses. Ongoing efforts are designed to establish mechanisms by which hsp70 may modulate these protective immune responses, either directly as a consequence of extracellular hsp70 release from infected cells, or indirectly as a consequence of hsp70-dependent changes in viral gene expression and/or cytopathic effect.
Transinstitutional WorkOur analysis of the role of hsp70 in modulating host immune responses in the central nervous system is the basis for collaboration with other investigators in the neurosciences. Spinal cord trauma induces an inflammatory response that may be either host protective or detrimental, and it is possible that hsp70 modulates these responses. This is the basis for collaboration with laboratories in the Center for Brain and Spinal Cord Repair, The Ohio State University Medical Center.
The study of viral neurovirulence is also relevant to studies of viral oncolytic therapy of brain tumors, with MeV being an established oncolytic agent, and potential barriers to oncolytic therapy being innate and adaptive antiviral immune responses. This interest is the basis for collaboration with faculty in the department of Neurological Surgery, The Ohio State University Medical Center, where focus is placed upon viral oncolytic therapy of human gliomas.
More broad trans-institutional involves collaborative research with investigators at the University of Marseille (France), where protein chemists with expertise in intrinsically disordered domains are supporting our ongoing to attempts to identify the structural basis for hsp70-mediated stimulation of viral gene expression.