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Research Interests:

The central focus of our research is the synthesis, folding, processing and function of viral glycoproteins. Previous studies of the synthesis and processing of viral glycoproteins in the secretory pathway have led to fundamental discoveries of basic cellular processes, and our research on the folding and processing of paramyxovirus glycoproteins provides insight into both cellular functions and important viral proteins. Our studies on viral proteins aim to elucidate mechanisms of promotion of membrane fusion, and to provide new targets for antiviral treatments.

Many major human pathogenic viruses (including HIV, herpes simplex virus, measles virus and Ebola virus) are packaged in a membrane. In order for these viruses to infect cells, specific viral proteins promote fusion of the viral membrane with the membrane of the host cell. Understanding this process of protein-mediated membrane fusion is the major focus of our work. We study fusion proteins from several different paramyxoviruses. First, we are examining the fusion protein from the Hendra and Nipah viruses, newly emerged diseases in the paramyxovirus family that are highly pathogenic in multiple species including humans, and which are classified as Biosafety Level 4 pathogens. Our laboratory has identified cathepsin L, a cellular endosomal/lysosomal protease, as critical protein for activation of the Hendra and Nipah fusion proteins, and thus a potential drug target. We are also studying the F protein from the paramxyovirus SV5, for which multiple mutants have been made and for which several atomic structures are now known. Finally, we have initiated study of the glycoproteins from human metapneumovirus, a recently identified virus that is a causative agent of severe respiratory disease in infants and young children. Our long-term goal is to understand the specific molecular events in these important membrane fusion processes.
 

Representative Publications:

Schowalter, Rachel M., Stacy E. Smith, and Rebecca Ellis Dutch (2006) Characterization of human metapneumovirus F protein-promoted membrane fusion: critical roles for F protein processing and low pH. Manuscript submitted.

Pager, Cara T., Willie W. Craft, Jr., Jared Patch and Rebecca Ellis Dutch (2006) A mature and fusogenic form of the Nipah virus fusion protein requires proteolytic processing by cathepsin L. Virology. 346: 251-257.

Schowalter, Rachel M., Mark A. Wurth, Hector C. Aguilar, Benhur Lee, Carole L. Moncman, Richard O. McCann and Rebecca Ellis Dutch (2006) Rho GTPase activity modulates paramyxovirus F protein mediated cell-cell fusion. Virology. 350: 323-334 (COVER).

Meulendyke, Kelly A., Mark A. Wurth, Richard O. McCann and Rebecca Ellis Dutch (2005) Endocytosis plays a critical role in proteolytic processing of the Hendra virus fusion protein. J. Virol. 79: 12643-12649.

Pager, Cara T. and Rebecca Ellis Dutch (2005) Cathepsin L is involved in proteolytic processing of the Hendra virus fusion protein. J. Virol. 79: 12714-12720.

Craft, Willie W. and Rebecca Ellis Dutch (2005) Sequence motif upstream of the Hendra virus fusion protein cleavage site is not sufficient to promote efficient proteolytic processing. Virology. 341: 130-140.

Carter, James, Stephen D. Fowler, Cara T. Pager and Rebecca Ellis Dutch (2005) The role of N-linked glycosylation of the Hendra virus fusion protein. J. Virol. 79:7922-7925.

West, Dava S., Michael S. Sheehan, Patrick K. Segeleon and Rebecca Ellis Dutch. (2005) Role of N-terminal heptad repeat residues in the folding and membrane fusion promotion of the SV5 F protein. J. Virol. 79: 1543-1551.

Pager, Cara T., Mark A. Wurth and Rebecca Ellis Dutch (2004) Sub-cellular localization and determination of Ca2+ and pH requirements for proteolytic cleavage of the Hendra virus fusion protein. J. Virol. 78: 9154-9163.