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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Krause, Kathrin; Kopp, Benjamin T; Tazi, Mia F et al. (2018) The expression of Mirc1/Mir17-92 cluster in sputum samples correlates with pulmonary exacerbations in cystic fibrosis patients. J Cyst Fibros 17:454-461
Tazi, Mia F; Dakhlallah, Duaa A; Caution, Kyle et al. (2016) Elevated Mirc1/Mir17-92 cluster expression negatively regulates autophagy and CFTR (cystic fibrosis transmembrane conductance regulator) function in CF macrophages. Autophagy 12:2026-2037
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
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
Abdelaziz, Dalia H A; Khalil, Hany; Cormet-Boyaka, Estelle et al. (2015) The cooperation between the autophagy machinery and the inflammasome to implement an appropriate innate immune response: do they regulate each other? Immunol Rev 265:194-204
Abdulrahman, Basant A; Khweek, Arwa Abu; Akhter, Anwari et al. (2013) Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr ?F508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery. J Biol Chem 288:2049-58
Aeffner, Famke; Abdulrahman, Basant; Hickman-Davis, Judy M et al. (2013) Heterozygosity for the F508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity. J Infect Dis 208:780-9
Amer, Amal O (2013) The many uses of autophagosomes. Autophagy 9:633-4
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

Showing the most recent 10 out of 32 publications