Autophagy has recently been recognized as a key player in innate and acquired immune responses. Disruption of autophagy in macrophages, the first line of cells in host defense, leads to increased inflammation and bacterial survival. We found that macrophages harboring a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have weak autophagy activity and are unable to clear some bacteria such as Burkholderia cenocepacia. Mutations in the cftr gene lead to cystic fibrosis, the most common inherited lethal disease among Caucasians. CF patients are born with innate immune deficiency rendering them prone to Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cenocepacia. These infections lead to excessive inflammation and the eventual loss of pulmonary function. Notably, all three microbes are controlled by autophagy in healthy immune cells. Our recent studies demonstrated that macrophages from CF patients have weak autophagy activity. It is not clear how the malfunction of an ion channel transporter compromises autophagy. This proposal will identify (i) the role of CFTR ion channel in controlling autophagy in macrophages, and (ii) the role of CFTR in epigenetic regulation of autophagy genes to restore autophagy and innate immunity. This proposal will help in the understanding of basic biological mechanisms linking ion transport to autophagy and also offer new therapeutic targets for CF patients.

Public Health Relevance

The basic biological functions of ion channels have been well studied in epithelial cells but not immune cells such as macrophages. Only recently, that we recognize that reduced functions of an ion channel diminishes the ability of macrophages to combat infection, execute autophagy response and control inflammation. Our study will apply to disease conditions that are characterized by weak autophagy activity such as Crohn's diseases, neurodegenerative disorders and senescence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI124121-01
Application #
9093169
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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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
Shrestha, Chandra L; Assani, Kaivon D; Rinehardt, Hannah et al. (2017) Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages. PLoS One 12:e0186169