William B. Klimstra, PhD

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.