Legionella pneumophila is an intracellular pathogen that evades endocytic fusion and hijacks ER-to-golgi vesicle traffic to remodel its phagosome into an ER-derived compartment permissive for intracellular replication. The Dot/lcm type IV secretion system of L. pneumophila is essential for both modulation of phagosome biogenesis and modulation of the macrophage apoptotic pathways through robust early and novel activation of caspase-3, independent of the intrinsic and extrinsic pathways of apoptosis. The Dot/lcm- mediated activation of caspase-3 results in cleavage of Rabaptin-5, which is an effector of the early endosome regulator Rab5. Inhibition of caspase-3 using caspase-3 peptide inhibitors blocks intracellular replication of L. pneumophila and results in trafficking of the organism to phagolysosomes, similar to dot/icm mutants. Our hypothesis is: Caspase-3-meditaed cleavage of Rabaptin-5 is central to the arrested biogenesis of the Legionella-containing phagosome (LCP) and to intracellular replication. To test this hypothesis, our specific aims are to examine the following:
Specific aim I. Role of caspase-3 activation in biogenesis of the LCP;
Specific aim II : Role of caspase-3-mediated cleavage of Rabaptin-5 in biogenesis of the LCP;
Specific aim III. Identification of the L. pneumophila effector involved in caspase-3 activation. Significance: Our proposed studies are the crux of our understanding of the molecular and cellular mechanisms by which this pathogen commandeer the host cell, and will she light on the cellular mechanism by which this pathogen engages a cross talk between the apoptotic pathways and vesicle traffic in the host cell to remodel it to its liking. The bacterial effector involved in this process is a potential target for therapy and prevention of the disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI069321-01A2
Application #
7313327
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Korpela, Jukka K
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2007-07-15
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$370,000
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
Bruckert, William M; Abu Kwaik, Yousef (2015) Complete and ubiquitinated proteome of the Legionella-containing vacuole within human macrophages. J Proteome Res 14:236-48
Richards, A M; Abu Kwaik, Y; Lamont, R J (2015) Code blue: Acinetobacter baumannii, a nosocomial pathogen with a role in the oral cavity. Mol Oral Microbiol 30:2-15
Price, Christopher T D; Richards, Ashley M; Abu Kwaik, Yousef (2014) Nutrient generation and retrieval from the host cell cytosol by intra-vacuolar Legionella pneumophila. Front Cell Infect Microbiol 4:111
Price, Christopher T D; Richards, Ashley M; Von Dwingelo, Juanita E et al. (2014) Amoeba host-Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution. Environ Microbiol 16:350-8
Price, Christopher T D; Abu Kwaik, Yousef (2014) The transcriptome of Legionella pneumophila-infected human monocyte-derived macrophages. PLoS One 9:e114914
Bruckert, William M; Price, Christopher T; Abu Kwaik, Yousef (2014) Rapid nutritional remodeling of the host cell upon attachment of Legionella pneumophila. Infect Immun 82:72-82
Abu Kwaik, Yousef; Bumann, Dirk (2013) Microbial quest for food in vivo: 'nutritional virulence' as an emerging paradigm. Cell Microbiol 15:882-90
Al-Quadan, Tasneem; Price, Christopher T; Abu Kwaik, Yousef (2012) Exploitation of evolutionarily conserved amoeba and mammalian processes by Legionella. Trends Microbiol 20:299-306
Al-Quadan, Tasneem; Price, Christopher T; London, Nir et al. (2011) Anchoring of bacterial effectors to host membranes through host-mediated lipidation by prenylation: a common paradigm. Trends Microbiol 19:573-9
Price, Christopher T D; Al-Quadan, Tasneem; Santic, Marina et al. (2011) Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science 334:1553-7

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