High case fatality rates are observed during sporadic Ebola virus outbreaks. Currently, elusive or not available is the Ebola reservoir host or any safe efficacious treatments. Bats, given their unique features, have been identified as one potential reservoir host, but why Ebola is highly virulent in some mammals and not in others is not well understood. In an effort to address this gap in our knowledge, we have initiated a study to test the role of filoviral genes that are preserved in some mammalian genomes, including those of bats. Filoviral genomes encode seven structural proteins, one of which is viral protein 35 (VP35), a multifunctional protein that both enhances viral propagation in Ebola and inhibits the immune response in its host. Contrastingly, VP35 protein in bats (batVP35) has been conserved over millions of years, and is thought to be a key component aiding in protection from Ebola infection. As a part of the efforts to better understand if VP35 confers resistance to the virus in bats, structural studies of the bat VP35 have been undertaken. Surmounting significant challenges posed while solving the protein crystal structure yielded: a few single crystals suitable for diffraction experiments and a single native data set collected at the IMCA-CAT insertion device beamline at the Advanced Photon Source. The three-dimensional atomic structure of bat viral protein VP35 was solved by molecular replacement using a model of only 33% homology. The structure has been refined to 2.50 Å resolution. Comparison of the structure of this batVP35 protein with that of the Ebola VP35 protein reveals structural similarity to the viral VP35. However, batVP35 also shows unusual biophysical properties as well as dsRNA binding and IFN inhibition, which collectively show significant functional differences that may contribute to its role in bat cells. We will discuss major differences and potential implications to viral replication and host responses as well as potential new targets for therapeutic development.
Garrett Ginell, ’18
Biochemistry & Molecular Biology