William B. Klimstra, PhD

Associate Professor


Dr. Klimstra

Contact

412-648-5962
Fax: 412-624-4440

8037 Biomedical Science Tower 3

3501 Fifth Avenue

Pittsburgh, PA 15261-1308

Education

PhD, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill

Research Summary

The goal of my laboratory has been 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 [SB], Venezuelan equine encephalitis virus [VEEV], eastern equine encephalitis virus [EEEV], western equine encephalitis virus [WEEV], Chikungunya virus [CHIKV] and Ross River virus [RRV]) 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 and identification of host innate immune mechanisms that control virus replication within individual cells. Furthermore, since the extent of virus replication, viral cellular tropism and the host response to infection are critical factors in stimulation of robust and appropriate immune responses to immunogens, we also strive to translate information gained from pathogenesis studies into strategies for improvement of alphavirus-based gene delivery systems.

Research Lab Affiliation

Publications

Daffis, S; Szretter, K. J; Schriewer, J; Li, J; Youn, S; Errett, J; Lin, T. Y; Schneller, S; Zust, R; Dong, H; Thiel, V; Sen, G. C; Fensterl, V; Klimstra, W. B; Pierson, T. C; Buller, R. M; Gale, M., Jr; Shi, P. Y; and Diamond, M. S. (2010) 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature. 468: 452-456. |  View Abstract

Zhang, X. Y; Kutner, R. H; Bialkowska, A; Marino, M. P; Klimstra, W. B; and Reiser, J. (2010) Cell-specific targeting of lentiviral vectors mediated by fusion proteins derived from Sindbis virus, vesicular stomatitis virus, or avian sarcoma/leukosis virus. Retrovirology. 7: 3. |  View Abstract

Meier, K. C; Gardner, C. L; Khoretonenko, M. V; Klimstra, W. B; and Ryman, K. D. (2009) A mouse model for studying viscerotropic disease caused by yellow fever virus infection. PLoS Pathog. 5: e1000614. |  View Abstract

Burke, C. W; Gardner, C. L; Steffan, J. J; Ryman, K. D; and Klimstra, W. B. (2009) Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses. Virology. 395: 121-132. |  View Abstract

Yin, J; Gardner, C. L; Burke, C. W; Ryman, K. D; and Klimstra, W. B. (2009) Similarities and differences in antagonism of neuron alpha/beta interferon responses by Venezuelan equine encephalitis and Sindbis alphaviruses. J Virol. 83: 10036-10047. |  View Abstract

Gardner, C. L; Yin, J; Burke, C. W; Klimstra, W. B; and Ryman, K. D. (2009) Type I interferon induction is correlated with attenuation of a South American eastern equine encephalitis virus strain in mice. Virology. 390: 338-347. |  View Abstract

Ryman, K. D; and Klimstra, W. B. (2008) Host responses to alphavirus infection. Immunol Rev. 225: 27-45. |  View Abstract