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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442365
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$274,290
Indirect Cost
$33,301
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Ray, Greeshma; Schmitt, Phuong Tieu; Schmitt, Anthony P (2016) C-Terminal DxD-Containing Sequences within Paramyxovirus Nucleocapsid Proteins Determine Matrix Protein Compatibility and Can Direct Foreign Proteins into Budding Particles. J Virol 90:3650-60
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510
Fraley, Stephanie I; Athamanolap, Pornpat; Masek, Billie J et al. (2016) Nested Machine Learning Facilitates Increased Sequence Content for Large-Scale Automated High Resolution Melt Genotyping. Sci Rep 6:19218
Levy, Revital; Rotfogel, Ziv; Hillman, Dalia et al. (2016) Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction. Proc Natl Acad Sci U S A 113:E6437-E6446
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Ramachandran, Girish; Boyd, Mary Adetinuke; MacSwords, Jennifer et al. (2016) Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines. Clin Vaccine Immunol 23:520-3
Plaut, Roger D; Stibitz, Scott (2015) Improvements to a Markerless Allelic Exchange System for Bacillus anthracis. PLoS One 10:e0142758

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