William B. Klimstra, Ph.D.
Campus: Biomedical Science Tower 3, 3501 Fifth Ave
Pittsburgh, PA 15261
- B.A. - Southern Illinois University
- Ph.D. - University of North Carolina at Chapel Hill
- Post Doc – University of North Carolina at Chapel Hill
- Associate Professor, Department of Immunology
- Member, Center for Vaccine Research
A major 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 and flaviviruses (e.g., Sindbis virus, Venezuelan equine encephalitis virus, eastern equine encephalitis virus, western equine encephalitis virus, chikungunya virus, Ross River virus, yellow fever virus and dengue virus) and the contribution of replication in specific cells to the pathogenesis of viral disease.
We have projects investigating both the inductive and effector phases of the interferon antiviral response, identifying host and viral factors that result in recognition of infection and subsequent upregulation of effectors of the antiviral state. In addition, we use a variety of approaches to identify important antiviral effector molecules and determine their mechanisms of action. We have discovered several cell surface receptors used by arboviruses including heparan sulfate molecules and C-type lectins. A current emphasis is determining how utilization of these receptors for cell entry influences the response of cells to infection, in particular the interferon response, and ultimately, characteristics of disease.
As members of the Center for Vaccine Research we are also interested in utilizing the understanding gained by study of fundamental arboviral pathogenesis in developing new generations of vaccine vectors and antiviral therapeutics. The alphaviruses are particularly amenable to use as delivery vehicles for immunogens and considerable effort is dedicated toward improving the vehicles themselves as well a determining their impact upon innate and acquired immune responses in vaccinated animals.
All of our in vitro observations are validated in animal models of arbovirus infection using the facilities of the Regional Biocontainment Laboratory. Therefore, trainees will gain experience in basic molecular virology as well as animal studies and work at BSL-3 enhanced conditions in laboratories of the RBL.
Daffis S, Szretter KJ, Schriewer J, Li J, Youn S, Errett J, Lin TY, Schneller S, Zust R, Dong H, Thiel V, Sen GC, Fensterl V, Klimstra WB, Pierson TC, Buller RM, Gale M Jr, Shi PY, Diamond MS. 2010. 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature. 468:452-456.
Gardner, C.L., Ebel G.D., Ryman, K.D. and Klimstra, W.B. 2011. Heparan sulfate binding by natural eastern equine encephalitis viruses promotes neurovirulence. Proc. Natl. Acad. Sci. U.S.A. 108(38):16026-31. PMID: 21896745.
C.L. Gardner, Burke, C.W., Higgs, S.T., Klimstra, W.B., and Ryman, K.D. 2012. Interferon-alpha/beta deficiency greatly exacerbates arthritogenic disease in mice infected with wild-type chikungunya virus but not with the cell culture-adapted live-attenuated 181/25 vaccine candidate. 425(2):103-12. Virology. Epub 2012 Feb 1. PMID:22305131
Christina Gardner, Jozef Hritz, Christopher Weiss, Dana Vahalaningam, Stephen Higgs, Elodie Ghedin, William Klimstra and Kate Ryman. 2013. Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design. PLOS Neglected Tropical Diseases 8e 2719.
Trobaugh, D.W., C.L. Gardner, E. Wang, A. Haddow, S.C. Weaver, K.D. Ryman and W.B. Klimstra. RNA viruses can hijack vertebrate microRNAs to suppress innate immunity. 2014. Nature. 747:245-8.
Chengqun Sun, Christina L. Gardner, Alan D. Watson, Kate D. Ryman and William B. Klimstra. 2014. Stable, high-level expression of reporter proteins from improved alphavirus expression vectors to track replication and dissemination during encephalitic and arthritogenic disease. J. Virol. 88:2035-46.
Jennifer L. Hyde, Christina L. Gardner, Taishi Kimura, James P. White, Derek W. Trobaugh, Cheng Huang, Kristy J. Szretter, Slobodan Paessler, Kiyoshi Takeda, William B. Klimstra, Gaya Amarasinghe, and Michael S. Diamond. 2014. A viral RNA structural element antagonizes the antiviral actions of Ifit1. Science. 343:783-7.
K. D. Ryman and William B. Klimstra 2014. Closing the gap between viral and noninfectious arthritis. Proc Natl. Acad. Sci. USA. 111:5767-5768.
Avraham Bayer, Elizabeth Delorme-Axford, Christie Sleigher, Teryl K. Frey, Derek W. Trobaugh, William B. Klimstra, Lori A. Emert- Sedlak, Thomas E. Smithgall, Paul R. Kinchington, Stephen Vadia, Stephanie Seveau, Carolyn B. Coyne, Yoel Sadovsky. 2014. Primary human trophoblasts confer resistance to clinically relevant viruses linked to perinatal infections in non-trophoblast cells, but not to intracellular bacteria or parasites. Am. J. Obstet. Gyn. in press.
Derek W. Trobaugh, Kate D. Ryman, and William B. Klimstra. Can understanding the virulence mechanisms of RNA viruses lead us to a vaccine against eastern equine encephalitis virus and other alphaviruses? 2014. Exp. Rev. Vaccines. 13:1423-5.