Yersinia pestis, is the etiologic agent of plague, a disease that has killed millions of people during massive pandemics and persists worldwide. The pathogenicity of Y. pestis is largely dependent upon its ability to thwart the defenses of its host and to overwhelm it with massive growth. Two surface-exposed outer membrane proteins, Adhesion invasion locus (Ail) and Plasminogen activator (Pla) play a critical role in this process. This project focuses on Ail and its role in promoting Y. pestis pathogenesis. Ail is required for complement resistance, efficient attachment to host cells, Yop injection and for virulence in rodent models of bubonic, septicemic and pneumonic plague. Ail binds several host ligands including fibronectin, laminin and C4b- binding protein. We have recently identified vitronectin (Vn) as a new key ligand of Ail. Vn is a multifunctional protein with roles in cell adhesion and complement control. Vn also binds and stabilizes Plasminogen activator inhibitor 1 (PAI-1), a potent regulator of coagulation and fibrinolysis. Ail recruits Vn to the bacterial surface and promotes its degradation by Pla. The studies outlined in this proposal will: (i) use ligand-based NMR binding studies to define the Ail- Vn interaction at the molecular level; (ii) use bacterial cell-based and biochemical assays to define the role of the Ail-Vn interaction in fibrinolysis, complement resistance, cell attachment and Yop injection; and (iii) define the role of the Ail-Vn interaction in a murine model of septicemic plague. Ail is currently a target for therapy development and understanding how it functions is critical to this effort.

Public Health Relevance

Yersinia pestis, the bacteria that causes bubonic and pneumonic plague, uses a protein on its surface, called Ail, to protect itself from the innate defenses of its host. We have shown that Ail binds vitronectin, a host protein that controls the complement system and mediates cell adhesion. Our studies will characterize the Ail-Vn binding event and determine the role of this interaction in the development of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI130009-03
Application #
9632685
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Yao, Yong; Dutta, Samit Kumar; Park, Sang Ho et al. (2017) High resolution solid-state NMR spectroscopy of the Yersinia pestis outer membrane protein Ail in lipid membranes. J Biomol NMR 67:179-190