The Department of Microbiology and Immunology is pleased to announce that Dr. Wendy Maury has been awarded a National Institutes of Health Exploratory/Developmental Research Project Grant (R21).  This research will focus on the substitution of Marburg virus (MARV) glycoprotein (GP) for Ebola virus (EBOV) GP in the context of two different viral backbones results in reduced sensitivity to type I and II IFNs in murine Kupffer cells. Our preliminary supporting data indicate that this differential effect is due to IFN inhibition of EBOV GP-dependent entry events, but not MARV GP-dependent entry. These studies will define and characterize interactions of these GPs with host innate immune factors that result in this differential effect.  Dr. Maury will collaborate with Dr. Mark Schultz in the Department of Pediatrics.

Project Summary:

In recent studies, we have demonstrated that viruses encoding Marburg virus (MARV) glycoprotein (GP) are less sensitive to type I and II interferon (IFN)-dependent inhibition than the same viruses encoding Ebola virus (EBOV) GP. Our preliminary findings indicate that one or more interferon stimulated genes (ISGs) inhibits EBOV GP dependent entry, but not MARV-dependent entry. Our new-found appreciation for the differential IFN control of viruses encoding EBOV and MARV GPs identifies an additional layer of complexity to the ongoing war between filoviruses and host innate immunity. Identifying ISG(s) that selectively restrict EBOV, but not MARV, would yield fundamental insights into the molecular determinants of species barriers to filovirus infection, inform the mechanisms underlying viral spillover events, and highlight potential targets for therapeutic intervention. This application seeks to elucidate those interactions and may identify new strategies for combating the episodic, devastating outbreaks caused by these viruses. During these proposed Aim 1 studies, we will characterize which human and mouse cells inhibit EBOV GP, but not MARV GP, dependent entry when pretreated with type I or II IFN. We will also define which filovirus GPs are sensitive to IFN pretreatment. In Aim 2, we will use two different strategies to identify and characterize host factors that are responsible for this differential effect on filovirus GPs. By the successful completion of these studies, a clear understanding of a newly appreciated mechanism of IFN inhibition of EBOV GP entry will be achieved. These studies are significant and innovative as they investigate a previously unappreciated antiviral mechanism that controls entry of some, but not other, members of this deadly family of viruses. These studies may provide the basis for future antiviral approaches.