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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Tsai, Wen-Yang; Youn, Han Ha; Tyson, Jasmine et al. (2018) Use of Urea Wash ELISA to Distinguish Zika and Dengue Virus Infections. Emerg Infect Dis 24:1355-1359
Thongsripong, Panpim; Chandler, James Angus; Green, Amy B et al. (2018) Mosquito vector-associated microbiota: Metabarcoding bacteria and eukaryotic symbionts across habitat types in Thailand endemic for dengue and other arthropod-borne diseases. Ecol Evol 8:1352-1368
Katzelnick, Leah C; Ben-Shachar, Rotem; Mercado, Juan Carlos et al. (2018) Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua. Proc Natl Acad Sci U S A 115:10762-10767
Clemens, Daniel L; Lee, Bai-Yu; Horwitz, Marcus A (2018) The Francisella Type VI Secretion System. Front Cell Infect Microbiol 8:121
Huwyler, Camille; Heiniger, Nadja; Chomel, Bruno B et al. (2017) Dynamics of Co-Infection with Bartonella henselae Genotypes I and II in Naturally Infected Cats: Implications for Feline Vaccine Development. Microb Ecol 74:474-484
Norris, Michael H; Heacock-Kang, Yun; Zarzycki-Siek, Jan et al. (2017) Burkholderia pseudomallei natural competency and DNA catabolism: Identification and characterization of relevant genes from a constructed fosmid library. PLoS One 12:e0189018
Marques, Adriana R; Yang, Xiuli; Smith, Alexis A et al. (2017) Citrate Anticoagulant Improves the Sensitivity of Borreliella (Borrelia) burgdorferi Plasma Culture. J Clin Microbiol 55:3297-3299
Nualnoi, Teerapat; Norris, Michael H; Tuanyok, Apichai et al. (2017) Development of Immunoassays for Burkholderia pseudomallei Typical and Atypical Lipopolysaccharide Strain Typing. Am J Trop Med Hyg 96:358-367
Parameswaran, Poornima; Wang, Chunling; Trivedi, Surbhi Bharat et al. (2017) Intrahost Selection Pressures Drive Rapid Dengue Virus Microevolution in Acute Human Infections. Cell Host Microbe 22:400-410.e5
Bortell, Nikki; Flynn, Claudia; Conti, Bruno et al. (2017) Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points. Mediators Inflamm 2017:7582437

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