The causative agent of the fatal disease Tularemia, Francisella tularensis (Ft), is a gram negative highly infectious intracellular bacterium, that is classified as a Category A Select Bioterrorism Agent. Intracellular replication of Ft within macrophages is essential for disease manifestation. It is rather astonishing the relative paucity of knowledge about the molecular and cellular aspects of pathogenesis of this versatile and extremely virulent pathogen. Our preliminary data indicate that upon entry into macrophages, Ft-containing phagosome (FCP) evades lysosomal fusion. The organism escapes from the phagosome into the cytoplasm by 2-12h post-infection. Our hypothesis is that specific modes of entry of Ft into macrophages allow the organism to modulate biogenesis of its phagosome, by specific exported bacterial effectors, into a niche that does not fuse to the lysosomes and allow subsequent escape of the organism into the cytoplasm, where it replicates. To test this hypothesis, our specific aims are: I. To dissect the cell biology of intracellular F. tularensis and the unique mechanisms that halt phagosome biogenesis at a non-acidified late endosome-like stage. II. To identify mutants defective in arresting phagosome biogenesis and escape into the cytoplasm. . To characterize the bacterial factors involved in arresting phagosome biogensis and escape into the cytoplasm. Significance: Pathogenesis of the Category A Select Bioterrorism Agent Ft is one of the least studied and understood among intracellular bacterial pathogens. Understanding how this organism exploits macrophages for proliferation and disease manifestation is fundamental to our knowledge of tularemia. The bacterial effectors involved in exploiting the macrophage are potential targets for treatment as well as potential vaccine candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065974-04
Application #
7579056
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mukhopadhyay, Suman
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$351,528
Indirect Cost
Name
University of Louisville
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Asare, Rexford; Akimana, Christine; Jones, Snake et al. (2010) Molecular bases of proliferation of Francisella tularensis in arthropod vectors. Environ Microbiol 12:2587-612
Asare, Rexford; Abu Kwaik, Yousef (2010) Molecular complexity orchestrates modulation of phagosome biogenesis and escape to the cytosol of macrophages by Francisella tularensis. Environ Microbiol 12:2559-86
Santic, Marina; Al-Khodor, Souhaila; Abu Kwaik, Yousef (2010) Cell biology and molecular ecology of Francisella tularensis. Cell Microbiol 12:129-39
Molmeret, Maelle; Jones, Snake; Santic, Marina et al. (2010) Temporal and spatial trigger of post-exponential virulence-associated regulatory cascades by Legionella pneumophila after bacterial escape into the host cell cytosol. Environ Microbiol 12:704-15
Santic, Marina; Akimana, Christine; Asare, Rexford et al. (2009) Intracellular fate of Francisella tularensis within arthropod-derived cells. Environ Microbiol 11:1473-81
Santic, Marina; Asare, Rexford; Skrobonja, Ivana et al. (2008) Acquisition of the vacuolar ATPase proton pump and phagosome acidification are essential for escape of Francisella tularensis into the macrophage cytosol. Infect Immun 76:2671-7
Molmeret, Maelle; Santic', Marina; Asare, Rexford et al. (2007) Rapid escape of the dot/icm mutants of Legionella pneumophila into the cytosol of mammalian and protozoan cells. Infect Immun 75:3290-304
Asare, Rexford; Santic, Marina; Gobin, Ivana et al. (2007) Genetic susceptibility and caspase activation in mouse and human macrophages are distinct for Legionella longbeachae and L. pneumophila. Infect Immun 75:1933-45
Abu-Zant, Alaeddin; Jones, Snake; Asare, Rexford et al. (2007) Anti-apoptotic signalling by the Dot/Icm secretion system of L. pneumophila. Cell Microbiol 9:246-64
Santic, Marina; Asare, Rexford; Doric, Miljenko et al. (2007) Host-dependent trigger of caspases and apoptosis by Legionella pneumophila. Infect Immun 75:2903-13

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