The goal of this proposal is to understand the strategies used by F. tularensis to evade the immune response, and to ultimately devise ways to defeat the immune evasion by the bacteria. F. tularensis is a gram-negative, facultative intracellular bacterium. This bacteria require only a very low infective dose via aerosol infection, and has a long lifetime in the environment. Although F. tularensis infection in the US is not highly prevalent, it has the potential to become an important pathogen especially following intentional release. While the immune response to F. tularensis has not been well studied, it does require T cells for clearance of infection and resistance to reinfection. Our preliminary work shows that like many viruses and some bacteria, F. tularensis has evolved multiple strategies for evading the host innate and adaptive immune response. Two of these, the production of PGE2 by infected host cells and the down-regulation of MHC class I on infected cells are the targets for study in this proposal. In this application we propose to understand the genetic and molecular basis for these two forms of immune evasion. Public Health Relevance: The war between hosts and invaders has endured since the rise of the first multicellular organisms. This interaction has been honed to a high level in the relationship between intracellular bacteria and mammals. The main purpose of both the innate and adaptive mammalian immune systems is to avoid the destruction of the host due to bacterial and viral growth. At the same time bacteria and viruses have evolved multiple mechanisms to evade the host immune response. Here we study the mechanism evolved by the intracellular pathogen F. tularensis to modify the host immune response in order to make the bacteria more able to survive and multiply. The study of the interactions of the host with these bacteria will help point out not only the mechanism used by F. tularensis, but also ways in which other pathogens avoid the host immune response. The molecules used will provide important insights into the mechanisms of effective immunity, and provide potential drugable targets for the development of therapeutics, and vaccine adjuvants.

Public Health Relevance

The war between hosts and invaders has endured since the rise of the first multicellular organisms. This interaction has been honed to a high level in the relationship between intracellular bacteria and mammals. The main purpose of both the innate and adaptive mammalian immune systems is to avoid the destruction of the host due to bacterial and viral growth. At the same time bacteria and viruses have evolved multiple mechanisms to evade the host immune response. Here we study the mechanism evolved by the intracellular pathogen F. tularensis to modify the host immune response in order to make the bacteria more able to survive and multiply. The study of the interactions of the host with these bacteria will help point out not only the mechanism used by F. tularensis, but also ways in which other pathogens avoid the host immune response. The molecules used will provide important insights into the mechanisms of effective immunity, and provide potential drugable targets for the development of therapeutics, and vaccine adjuvants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078345-05
Application #
8481501
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Mukhopadhyay, Suman
Project Start
2009-07-22
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$348,941
Indirect Cost
$118,617
Name
University of Arizona
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Roberts, Lydia M; Davies, John S; Sempowski, Gregory D et al. (2014) IFN-?, but not IL-17A, is required for survival during secondary pulmonary Francisella tularensis Live Vaccine Stain infection. Vaccine 32:3595-603
Barrigan, Lydia M; Tuladhar, Shraddha; Brunton, Jason C et al. (2013) Infection with Francisella tularensis LVS clpB leads to an altered yet protective immune response. Infect Immun 81:2028-42
Woolard, Matthew D; Barrigan, Lydia M; Fuller, James R et al. (2013) Identification of Francisella novicida mutants that fail to induce prostaglandin E(2) synthesis by infected macrophages. Front Microbiol 4:16
Valentino, Michael D; Abdul-Alim, C Siddiq; Maben, Zachary J et al. (2011) A broadly applicable approach to T cell epitope identification: application to improving tumor associated epitopes and identifying epitopes in complex pathogens. J Immunol Methods 373:111-26