Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). Here, we confirm that long-term azithromycin use by adults with CF is associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identify an underlying mechanism. We found that in primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. Our findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.
Date Issued
2011-08-01
Date Acceptance
2011-06-08
Citation
Journal of Clinical Investigation, 2011, 121 (9), pp.3554-3563
ISSN
1558-8238
Publisher
American Society for Clinical Investigation
Start Page
3554
End Page
3563
Journal / Book Title
Journal of Clinical Investigation
Volume
121
Issue
9
Copyright Statement
© 2011 American Society for Clinical Investigation
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
MEDICINE, RESEARCH & EXPERIMENTAL
TUBERCULOSIS
MACROPHAGES
ABSCESSUS
THERAPY
DISEASE
DEFENSE
CANCER
Adult
Animals
Anti-Bacterial Agents
Autophagy
Azithromycin
COS Cells
Cercopithecus aethiops
Cystic Fibrosis
Drug Resistance, Bacterial
Enzyme Inhibitors
HeLa Cells
Humans
Lysosomes
Macrolides
Macrophages
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins
Mycobacterium
Mycobacterium Infections
Phagosomes
Recombinant Fusion Proteins
Sirolimus
Hela Cells
Immunology
11 Medical And Health Sciences
Publication Status
Published