cause fatal hemorrhagic fevers. Hence Ebola and Marburg viruses are significant Biodefense threats, urrently there are no approved anti-viral agents or vaccines to combat these devastating pathogens. Recent successes in the HIV system support the concept of inhibiting enveloped virus entry by blocking either virus binding to or fusion with host cells. The long-term objective of this project is to develop small molecule inhibitors and/or therapeutic antibodies that block binding or fusion of Ebola and Marburg viruses with host cells. Our work to date supports the following model for Ebola virus entry. After binding to an as yet unidentified receptor(s), Ebola is endocytosed and delivered to the endosomal system. There, cathepsins B and L cleave the receptor binding subunit (GP1) of the single Ebola virus glycoprotein (GP) to a 19kDa intermediate that confers considerably enhanced binding and infection;19kDa GP1 thus defines a receptorbinding domain (RBD) of the Ebola virus GP. A final cathepsin L dependent activity triggers fusion and hence virus entry into the cell cytoplasm. The major goal of this proposal is to explore blockade of Ebola and Marburg virus binding to host cells as a means to prevent infection and therefore to ameliorate disease sequelae. To attain this goal, we will address the following specific aims: (1) identify the host cell receptor(s) for Ebola and Marburg viruses; (2) pan for and characterize mAbs that bind to the Ebola and Marburg virus RBDs;and (3) develop and employ a high throughput screen for small molecules that block receptor binding. The project will involve state of the art genomic, proteomic, molecular virology, and high throughput screening approaches. The project has a very high degree of health relatedness. Given the extremely high morbidity and mortality rates of filovirus infections, there is a pressing need for a collection of agents to combat filovirus infections in both pre- and post exposure situations, for example for health care, animal care, and laboratory research workers as well as for local populations at large during an outbreak.

Public Health Relevance

Ebola and Marburg viruses are category A priority pathogens that incur exceedingly high morbidity and mortality rates and for which there are no approved vaccines or anti-viral agents. The goal of this project is to develop therapeutics that target the earliest stages of Ebola and Marburg virus infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
United States
Zip Code
Freedman, John C; Theoret, James R; Wisniewski, Jessica A et al. (2015) Clostridium perfringens type A-E toxin plasmids. Res Microbiol 166:264-79
Li, Jihong; McClane, Bruce A (2014) Contributions of NanI sialidase to Caco-2 cell adherence by Clostridium perfringens type A and C strains causing human intestinal disease. Infect Immun 82:4620-30
Moy, Ryan H; Gold, Beth; Molleston, Jerome M et al. (2014) Antiviral autophagy restrictsRift Valley fever virus infection and is conserved from flies to mammals. Immunity 40:51-65
Cuevas, Christian D; Ross, Susan R (2014) Toll-like receptor 2-mediated innate immune responses against Junín virus in mice lead to antiviral adaptive immune responses during systemic infection and do not affect viral replication in the brain. J Virol 88:7703-14
Boyd, Mary Adetinuke; Tennant, Sharon M; Saague, Venant A et al. (2014) Serum bactericidal assays to evaluate typhoidal and nontyphoidal Salmonella vaccines. Clin Vaccine Immunol 21:712-21
Su, Yi-Hsuan; Tsegaye, Mikiyas; Varhue, Walter et al. (2014) Quantitative dielectrophoretic tracking for characterization and separation of persistent subpopulations of Cryptosporidium parvum. Analyst 139:66-73
Xu, Jie; Cherry, Sara (2014) Viruses and antiviral immunity in Drosophila. Dev Comp Immunol 42:67-84
Uzal, Francisco A; Freedman, John C; Shrestha, Archana et al. (2014) Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease. Future Microbiol 9:361-77
Weir, Dawn L; Laing, Eric D; Smith, Ina L et al. (2014) Host cell virus entry mediated by Australian bat lyssavirus G envelope glycoprotein occurs through a clathrin-mediated endocytic pathway that requires actin and Rab5. Virol J 11:40
Weir, Dawn L; Annand, Edward J; Reid, Peter A et al. (2014) Recent observations on Australian bat lyssavirus tropism and viral entry. Viruses 6:909-26

Showing the most recent 10 out of 299 publications