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1615 Poydras Street - Suite 1000
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William Klimstra, PhD
Areas of Research: Virotherapy of Infectious Disease Dr. Klimstra and Dr. Ryman reported in the April 2007 issue on the Journal of Virology that changing a dendritic cell receptor interacting with the Sindbis virus, to interact with heparan sulfate (HS) enhances the ability of the virus to target and enter the cancer cells, increasing the number of infected cells in the lymph nodes. When injected directly into the tumor, this highly selective virus will be less likely to spread and replicate beyond the site of injection, providing additional safety. These findings suggest that the use of HS-binding Sindbis virus vectors offers several advantages for cancer gene therapy applications. The goal of Klimstra's laboratory is to define the host and viral factors that determine the success or failure of the innate immune response to infection with arthropod-borne viruses. The specific approach is to examine at the single cell level, the molecular mechanisms that determine host cell permissivity to the alphaviruses (e.g., Sindbis virus, Venezuelan equine encephalitis virus, eastern equine encephalitis virus and Ross River virus) and the contribution of replication in specific cells to the pathogenesis of viral disease. Upon introduction into a susceptible host, alphaviruses initially replicate within cells of the dendritic cell (DC) and macrophage lineages. In young animals, this replication is unrestrained and leads to induction of a toxic proinflammatory cytokine response. However, in adults virus replication and cytokine induction are restricted by one or more as yet uncharacterized mechanisms. These mechanisms likely involve changes in host cell permissivity to virus infection. Ongoing studies include: determination of the relationship between infection of DC/macrophage and induction of the systemic inflammatory response, identification and characterization of cellular receptors that promote virus infection, determination of intracellular host factors required for successful replication of the virus genome, and identification of host innate immune mechanisms that control virus replication within individual cells. Selected Publications M. Tesfay, J. Yin, C.L. Gardner, M. Khoretonenko, N. Korneeva, R.E. Rhoads, K. D. Ryman and W.B. Klimstra. 2008. Interferon alpha/beta inhibits cap-dependent translation of viral but not cellular mRNA by a PKR-independent mechanism. J. Virol. 82:2620-2630. Klimstra, W.B. and K.D. Ryman. Chp. 22: Togaviruses in Cellular signaling and imnnate immune responses to RNA virus infections. American Society for Microbiology. In Press.
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