The Ail family of proteins has been shown to mediate cell adhesion and resistance to human serum in several pathogenic Yersinia species. We have recently shown that Ail is important for delivery of cytotoxic Yop proteins from Yersinia pestis to phagocytic and non-phagocytic human cells. This defect in Yop delivery in vitro is reflected in the >3,000-fold increase in LD50 of a (ail mutant of Y. pestis KIM5 by the intravenous route of infection. Along with the decreased virulence of the (ail mutant, we also observed increased inflammation within infected spleen and liver tissues based on histology and greatly decreased bacterial loads in these tissues three days post- infection. This is the expected result if Yop delivery is inhibited, leading to lack of delivery of anti-inflammatory Yops. Due to the major role of Ail in plague pathogenesis, we propose to use a recently purified Ail protein to determine the ability of Ail immunization to protect naive mice from wild-type (fully virulent) Y. pestis infection delivered subcutaneously (bubonic plague) or intranasally (pneumonic plague). Given that experimental immunization with V antigen of Y. pestis or the non-immunosuppressive derivative V10 are standards in the field for plague vaccination, we will also characterize the combined protection provided by Ail together with V10. Y. pestis is the etiological agent of plague, a rapidly fatal disease and potential bioterrorism threat. There is currently no licensed plague vaccine in the U.S. and recent reports indicate escape mutants may undermine the efficacy of vaccines utilizing the F1 capsule as an immunogen. Thus, identification and development of additional protective antigens for future plague vaccine formulations are essential. Given the critical role for Y. pestis Ail in Yop delivery and virulence, it is an excellent candidate antigen for immunization trials using an animal model.
The specific Aims of this proposal are: 1. Assess the efficacy of Ail immunization for preventing plague in mice 2. Assess the efficacy of Ail + V10 (a derivative of V antigen) for cumulative plague protection in mice

Public Health Relevance

This project will test the efficacy of a new vaccine antigen, Ail, for its ability to protect mice from plague. If Ail proves to protect animals from disease, it could be incorporated into future vaccine formulations to prevent plague in humans. Plague is a rapidly-fatal infectious disease and potential bioterrorism threat with no currently licensed vaccine in the U.S.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI092318-02
Application #
8232034
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Zou, Lanling
Project Start
2011-03-01
Project End
2013-05-31
Budget Start
2012-03-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$77,750
Indirect Cost
$27,750
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tsang, Tiffany M; Annis, Douglas S; Kronshage, Malte et al. (2012) Ail protein binds ninth type III fibronectin repeat (9FNIII) within central 120-kDa region of fibronectin to facilitate cell binding by Yersinia pestis. J Biol Chem 287:16759-67
Yamashita, Satoshi; Lukacik, Petra; Barnard, Travis J et al. (2011) Structural insights into Ail-mediated adhesion in Yersinia pestis. Structure 19:1672-82