Francisella tularensis is a facultative intracellular gram-negative bacterium responsible for human tularemia. Interest in the pathogen has increased recently with the realization that it could be used as an agent of bioterrorism due to its high infectivity, potentially high mortality rates and the ability to deliver the organism to large numbers of persons by aerosol. Natural infections with F. tularensis proceed from an initial localized site via blood dissemination to the spleen, liver, lungs, CMS and kidneys. Immunity sufficient to resolve primary infections and mediate memory responses to secondary exposure is dependent on T cells, the cytokine interferon-gamma (IFN-g) and the activation of macrophages. However, relatively little is known about protective immune responses to primary infection that occur within the first week of exposure. Thus, it is not known which cells of the innate immune system respond to the bacterium, how they recognize microbial components or how they might initiate clearance. The long-term objective of this research is to characterize the cellular basis of IFN-g production during the initial phase of F. tularensis infection and define the mechanisms of immune recognition of the microbe in naive mice. Our central hypothesis is that IFN-g production by NK and NKT cells, which recognize the bacterium through their Toll-like receptors (TLR), is a key process in the early protective immunity.
Our specific aims are to: (i) identify the cellular subsets that are activated for IFN-g production during F. tularensis infection; (ii) define the role of TLR and accessory signals in the induction of these responses; and (iii) determine the role of TLR-mediated NK and NKT cell activation in early clearance of F. tularensis. Besides providing important insight into the nature of innate immunity to F. tularensis, this R21 application will assess the participation of NK/NKT cells and TLR-mediated signaling in these protective responses and generate important preliminary data to characterize the role of these cells in immune protection during the first few days of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI062939-01A1
Application #
6969857
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Schaefer, Michael R
Project Start
2005-07-15
Project End
2007-06-30
Budget Start
2005-07-15
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$202,125
Indirect Cost
Name
University of Kansas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Parmely, Michael J; Fischer, Jeffrey L; Pinson, David M (2009) Programmed cell death and the pathogenesis of tissue injury induced by type A Francisella tularensis. FEMS Microbiol Lett 301:1-11
Wickstrum, Jason R; Bokhari, Sirosh M; Fischer, Jeffrey L et al. (2009) Francisella tularensis induces extensive caspase-3 activation and apoptotic cell death in the tissues of infected mice. Infect Immun 77:4827-36
Bokhari, Sirosh M; Kim, Kee-Jun; Pinson, David M et al. (2008) NK cells and gamma interferon coordinate the formation and function of hepatic granulomas in mice infected with the Francisella tularensis live vaccine strain. Infect Immun 76:1379-89
Wickstrum, Jason R; Hong, Kee-Jong; Bokhari, Sirosh et al. (2007) Coactivating signals for the hepatic lymphocyte gamma interferon response to Francisella tularensis. Infect Immun 75:1335-42
Hong, Kee-Jong; Wickstrum, Jason R; Yeh, Hung-Wen et al. (2007) Toll-like receptor 2 controls the gamma interferon response to Francisella tularensis by mouse liver lymphocytes. Infect Immun 75:5338-45