Christopher F. Basler

Research

Specific Clinical/Research Interests: Molecular determinants of virulence of emerging viruses, including Ebola virus, Nipah virus and pandemic influenza virus

Current Students: PhD: Michael Ciancanelli, Charalampos Valmas, Kathleen Prins

Postdoctoral Fellows: Reed Shabman, Lawrence Leung, Osvaldo Martinez, Tshide Tsibane, St. Patrick Reid

Research Personnel: Alejandra Galvez

Summary of Research Studies:
My interests lie in defining molecular determinants of virulence of emerging viruses. Two main avenues of research are being pursued.

1. The interferon (IFN) alpha/beta response is a major component of innate defense against virus infection. As a consequence, viruses have evolved ways to counteract this response. We are interested in defining the mechanisms by which emerging viruses block the IFN system. We have identified IFN-antagonists from a variety of viruses including Ebola virus, Nipah virus and Eastern equine encephalitis virus. The mechanisms by which these proteins function are diverse and a major focus of the lab. Two Ebola virus encoded IFN-antagonists identified by our group serve as useful examples. We have demonstrated that the Ebola virus protein VP35 functions to inhibit IFN-alpha/beta production by blocking the signaling pathways that activate interferon regulatory factor 3, a transcription factor which plays a central role in the induction of the IFN response. A second Ebola virus protein, VP24, acts by a separate mechanism and inhibits the JAK-STAT signaling pathways normally activated upon addition of IFN to cells. In this case, VP24 prevents the nuclear accumulation of activated STAT1 through an interaction between VP24 and the STAT1 nuclear localization signal receptor karyopherin alpha 1. We hypothesize that the combined functions of these two proteins contribute to the high virulence of Ebola virus. Studies on these and other IFN-antagonists seek to define how each protein contributes to viral pathogenesis, to determine whether these anti-IFN functions also affect host adaptive immune responses to infection and to determine whether these proteins are viable targets for antiviral therapeutics.

2. We are also seeking to elucidate the molecular determinants of virulence of the 1918 pandemic influenza virus. The 1918 influenza virus is estimated to have caused more than 20 million deaths worldwide, but the reasons for this high mortality are poorly understood. We are involved in a collaborative "paleovirolgy" project that reconstructed the previously extinct 1918 virus with the expectation that such studies will reveal important new insights into influenza virus pathogenesis. Recent studies are focused on characterizing the 1918 influenza virus-specific immune responses that persist in survivors almost 90 years after the pandemic.