Role of caspases in Legionella pneumophila pulmonary infection. Legionella pneumophila (L. pneumophila) is a bacteriumthat causes Legionnaires'disease, a human illness characterized by severe pneumonia that affects the elderly and the immune-compromised individuals. Annually, 200,000 cases are reported in the United States and 8,000-18,000 people with legionellosis are hospitalized with fatality rates up to 30%. As a first line of defense in the lungs, macrophages engulf and degrade bacteria. However, some pathogens like L. pneumophila have strategies to subdue this phagocytic cell and establish infection. L. pneumophila is capable of multiplying within human macrophages whereas mice cells are resistant to L. pneumophila with the exception of mice lacking Ipaf, caspase-1 or harboring a mutant Naip5 gene. Ipaf is a NOD protein that senses intracellular bacterial flagellin leading to activation of caspase-1. Once activated, caspase-1 cleaves specific substrates leading to different events in the cell. However, caspases have been mainly considered for their role in cell death and studies on other functions of caspases have been lacking. Emerging studies suggest that caspases have important functions in the cell in addition to inducing cell death. We hypothesize that caspases can control the fate of intracellular bacteria like L pneumophila through the modulation of phagosome lysosome fusion events that will lead to bacterial clearance. Using mice lacking different caspases and their derived macrophages, we will investigate the novel role of caspases in dictating the fate of intracellular bacteria. We will discern the role of the NOD protein Naip5 in caspase activation. This project will determine the mechanism of control of L. pneumophila phagosome maturation. This study will ultimately enable the design of new molecules that can specifically target particular caspases and manipulate the maturation of phagosomes containing intracellular lung pathogens. This will represent a novel approach to the treatment and management of infection and inflammation in the lung.

Public Health Relevance

Legionella pneumophila is a bacterium that can cause severe pneumonia especially in the elderly and in individuals with low immunity leading to death. We propose to study how this lung pathogen can establish infection and cause disease. Our long term aim is to use this information to design molecules to combat Legionella and other lung microbes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094586-05
Application #
8477954
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$362,752
Indirect Cost
$121,019
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Abu Khweek, Arwa; Kanneganti, Apurva; Guttridge D, Denis C et al. (2016) The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages. PLoS One 11:e0146410
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Caution, Kyle; Gavrilin, Mikhail A; Tazi, Mia et al. (2015) Caspase-11 and caspase-1 differentially modulate actin polymerization via RhoA and Slingshot proteins to promote bacterial clearance. Sci Rep 5:18479
Khweek, Arwa A; Caution, Kyle; Akhter, Anwari et al. (2013) A bacterial protein promotes the recognition of the Legionella pneumophila vacuole by autophagy. Eur J Immunol 43:1333-44
Abdulrahman, Basant A; Khweek, Arwa Abu; Akhter, Anwari et al. (2013) Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr ΔF508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery. J Biol Chem 288:2049-58
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Novotny, Laura A; Amer, Amal O; Brockson, M Elizabeth et al. (2013) Structural stability of Burkholderia cenocepacia biofilms is reliant on eDNA structure and presence of a bacterial nucleic acid binding protein. PLoS One 8:e67629
Abu Khweek, Arwa; Fernandez Davila, Natalia S; Caution, Kyle et al. (2013) Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages. Front Cell Infect Microbiol 3:18
Akhter, Anwari; Caution, Kyle; Abu Khweek, Arwa et al. (2012) Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity 37:35-47

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