Francisella tularensis is a highly infectious gram-negative coccobacillus that causes the zoonosis tularemia and is a Category A agent. The need for understanding the molecular basis for F. tularensis disease in order to combat possible threats is evident. A hallmark of tularemia is the ability of the bacterium to grow in mammalian hosts before the onset of a protective cell-mediated immune response. Mammalian hosts are endowed with numerous antimicrobial effector functions. Accordingly, F. tularensis has evolved mechanisms to subvert host defenses. It is very striking that this small bacterium can infect its host via a variety of different infection routes, each of which involves a different host tissue site with a vastly different microenvironment. Given that F. tularensis is so successful at infecting its host via multiple tissue sites, our hypothesis is that in addition to a core set of genes that are needed for general survival and growth in vivo, F. tularensis possess additional genes that are required in specific tissues or microniches. Thus, our overarching goal is to identify novel core and tissue-specific virulence factors in F. tularensis. In the first aim, we will identify tissue-specific (e.g. lung-, spleen, and skin-specific) F. tularensis virulence factors using our well-established microarray-based negative selection methodology following intranasal, intraperitoneal and intradermal routes of inoculation. In the second and third aims, we will validate the tissue-specificity of novel virulence factors and characterize the molecular mechanisms in our mouse models of infection and in vitro in tissue culture assays. This project is synergistic with the other Francisella project in the Program in that it will allow us to directly compare the results of genetic and proteomic analyses obtained by Dr. Marcus Horwitz's laboratory utilizing F. tularensis subsp. tularensis, the LVS and F. novicida with our in vivo negative selection results. Since we will be using the same transposon mutant library for our in vivo and in vitro assays, followed by our very rapid microarray-based detection method, we will identify novel Francisella factors that interact with host proteins in an extremely efficient manner.

Public Health Relevance

There currently is not useful vaccine to prevent Francisella disease. We propose that F. tularensis, through the use of specific virulence factors, is tailoring the host innate immune responses in the infected tissues (e.g., lung, skin and spleen) to its advantage and that a better understanding of these molecular mechanisms will lead to the rational design of novel therapeutics that may be effective against other intracellular pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-06
Application #
8069270
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2010
Total Cost
$322,675
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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