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Sue
E.
Delos
Degree(s): Ph.D. Graduate School: Virginia Commonwealth University Primary Appointment: Associate Professor of Cell Biology Research Interests: Virus-Receptor Interactions; Virus-Cell Fusion Mechanisms Email Address: sed7a@virginia.edu |
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Biomedical Sciences Graduate Program(s) Research Description The major focus of my laboratory is to elucidate the mechanisms by which enveloped viruses enter cells, an obligate early step in the infection process. For the enveloped viruses, entry requires fusion of the viral and cellular membranes, an event driven by a carefully orchestrated series of conformational changes in specialized viral fusion proteins (envs). Envs are activated for fusion by proteolytic processing either during maturation or as part of the entry process. The proteolytic event cleaves the env into a fusion mediating subunit, now in a metastable state, and a receptor binding subunit that clamps the fusion subunit in its metastable conformation. Fusion is then triggered by release of this clamp either at the target cell plasma membrane or at an endosomal membrane after endocytosis. What are the requirements for a minimal clamp? How is the clamp released? What are the intermediates in the fusion pathway? What are the molecular requirements for the fusion protein to achieve each of these intermediate species? Where in the cell do these events occur? What is the role of the receptor? In collaboration with Dr. Judith M. White, I am using the Avian Sarcoma/Leukosis Virus (ASLV-A) and Ebola Virus, Zaire (EBOZ) as model retrovirus and filovirus systems to address these questions. ASLV-A is a particularly attractive retroviral model because a single a viral protein and a single receptor initiate these processes. Furthermore, there are two distinct rate-limiting steps in ASLV-A fusion: Receptor-induced exposure and insertion of the fusion peptide into target membranes (Step 1), then low pH-induced fold-back into a trimer of hairpins, merging the viral and cellular membranes to complete entry (Step 2). We are exploiting this unique characteristic of ASLV-A to elucidate the molecular requirements for each of these steps in the fusion process. The ASLV-A receptor is a member of the low density lipoprotein receptor family. These proteins harbor a series of ligand binding domains that interact with their respective ligands at a common surface. Soluble forms of the ASLV-A receptor and receptor binding subunit have allowed us to characterize the virus-receptor binding interactions and identify a novel ligand binding site utilized by the viral env. We are collaborating with Dr. John Bushweller to determine the viral binding surface. The triggering mechanisms for the ebolavirus fusion are less well understood than those for ASLV-A. Although the fusion subunit of the EBOZ and ASLV-A envs are structurally similar, the triggering mechanisms for these two viruses are quite different, allowing us to define common and individual requirements for fusion. The ZEBOV receptor is currently unknown; we are actively pursuing strategies for its identification. We have recently shown that the endosomal cathepsins B + L prime the ZEBOV fusion protein for fusion, but that additional steps are needed to trigger fusion. We are actively searching for this fusion trigger. Little is known about how internal fusion peptides such as those harbored by the ASLV and EBO envs function. In collaboration with Dr. Lucas Tamm, we are investigating the structural requirements for these internal fusion peptides, The long-term goal of our work is the identification of inhibitors of viral infection. Selected Publications Intranet Profile
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