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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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University of California Irvine
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Waggoner, Jesse J; Gresh, Lionel; Mohamed-Hadley, Alisha et al. (2016) Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 22:1295-7
Ziegler, Christopher M; Eisenhauer, Philip; Bruce, Emily A et al. (2016) The Lymphocytic Choriomeningitis Virus Matrix Protein PPXY Late Domain Drives the Production of Defective Interfering Particles. PLoS Pathog 12:e1005501
Barbour, Alan G (2016) Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans. Semin Cell Dev Biol :
Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43
Levin, Mattias; King, Jasmine J; Glanville, Jacob et al. (2016) Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy. J Allergy Clin Immunol 137:1535-44
Chomel, Bruno B; Molia, Sophie; Kasten, Rickie W et al. (2016) Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One 11:e0148299
Kern, Aurelie; Zhou, Chensheng W; Jia, Feng et al. (2016) Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. Vaccine 34:4507-13
Zeltina, Antra; Bowden, Thomas A; Lee, Benhur (2016) Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential. PLoS Pathog 12:e1005390
Waggoner, Jesse J; Ballesteros, Gabriela; Gresh, Lionel et al. (2016) Clinical evaluation of a single-reaction real-time RT-PCR for pan-dengue and chikungunya virus detection. J Clin Virol 78:57-61
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663

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