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Maurizio Renna, … , David C. Rubinsztein, R. Andres Floto
Published August 1, 2011
Citation Information: J Clin Invest. 2011;121(9):3554-3563. https://doi.org/10.1172/JCI46095.
Citation Information: J Clin Invest. 2011;121(9):3554-3563. https://doi.org/10.1172/JCI46095.
Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection
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.
Authors
Maurizio Renna, Catherine Schaffner, Karen Brown, Shaobin Shang, Marcela Henao Tamayo, Krisztina Hegyi, Neil J. Grimsey, David Cusens, Sarah Coulter, Jason Cooper, Anne R. Bowden, Sandra M. Newton, Beate Kampmann, Jennifer Helm, Andrew Jones, Charles S. Haworth, Randall J. Basaraba, Mary Ann DeGroote, Diane J. Ordway, David C. Rubinsztein, R. Andres Floto
Total citations by year
Citation information
Citations to this article (148)
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An Auto-luminescent Fluorescent BCG Whole Blood Assay to Enable Evaluation of Paediatric Mycobacterial Responses Using Minimal Blood Volumes
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Whole-Genome Sequencing and Epidemiological Analysis Do Not Provide Evidence for Cross-transmission of Mycobacterium abscessus in a Cohort of Pediatric Cystic Fibrosis Patients
KA Harris, A Underwood, DT Kenna, A Brooks, E Kavaliunaite, G Kapatai, R Tewolde, P Aurora, G Dixon |
Clinical Infectious Diseases | 2014 |
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Selective autophagy: Xenophagy
KA Bauckman, N Owusu-Boaitey, IU Mysorekar |
Methods | 2014 |
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Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion
M Schiebler, K Brown, K Hegyi, SM Newton, M Renna, L Hepburn, C Klapholz, S Coulter, A Obregon-Henao, MH Tamayo, R Basaraba, B Kampmann, KM Henry, J Burgon, SA Renshaw, A Fleming, RR Kay, KE Anderson, PT Hawkins, DJ Ordway, DC Rubinsztein, RA Floto |
EMBO Molecular Medicine | 2014 |
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Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER�stress‑mediated cell death in multiple myeloma cells
S Moriya, S Komatsu, K Yamasaki, Y Kawai, H Kokuba, A Hirota, XF Che, M Inazu, A Gotoh, M Hiramoto, K Miyazawa |
International journal of oncology | 2014 |
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Prevalence and drug resistance of mycobacteria in Turkish cystic fibrosis patients
D Satana, G Erkose-Genc, Z Tamay, M Uzun, N Guler, Z Erturan |
Annals of clinical microbiology and antimicrobials | 2014 |
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FIP200 is Involved in Murine Pseudomonas Infection by Regulating HMGB1 Intracellular Translocation
Y Li, C Gan, S Zhang, X Zhou, X Li, Y Wei, J Yang, M Wu |
Cellular Physiology and Biochemistry | 2014 |
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Update on nontuberculous mycobacterial infections in solid organ and hematopoietic stem cell transplant recipients.
Knoll BM |
Current Infectious Disease Reports | 2014 |
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Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation
B Liu, M Fang, Y Hu, B Huang, N Li, C Chang, R Huang, X Xu, Z Yang, Z Chen, W Liu |
Autophagy | 2013 |
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Autophagy in blood cancers: biological role and therapeutic implications
A Nencioni, M Cea, F Montecucco, VD Longo, F Patrone, AM Carella, TL Holyoake, GV Helgason |
Haematologica | 2013 |
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Autophagy: a potential therapeutic target in lung diseases
K Nakahira, AM Choi |
American journal of physiology. Lung cellular and molecular physiology | 2013 |
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Autophagy: a Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease
K Nakahira, S Cloonan, K Mizumura, AM Choi, SW Ryter |
Antioxidants & Redox Signaling | 2013 |
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Autophagy in Chronic Myeloid Leukaemia: Stem Cell Survival and Implication in Therapy
G Helgason, A Mukhopadhyay, M Karvela, P Salomoni, B Calabretta, T Holyoake |
Current cancer drug targets | 2013 |
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Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study
JM Bryant, DM Grogono, D Greaves, J Foweraker, I Roddick, T Inns, M Reacher, CS Haworth, MD Curran, SR Harris, SJ Peacock, J Parkhill, RA Floto |
The Lancet | 2013 |
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Nontuberculous mycobacteria: the changing epidemiology and treatment challenges in cystic fibrosis
JM Leung, KN Olivier |
Current Opinion in Pulmonary Medicine | 2013 |
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Epidemiology of Nontuberculous Mycobacterial Infections and Associated Chronic Macrolide Use among Persons with Cystic Fibrosis
AM Binder, J Adjemian, KN Olivier, DR Prevots |
American journal of respiratory and critical care medicine | 2013 |
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Bronchiectasis-associated hospitalizations in Germany, 2005-2011: a population-based study of disease burden and trends
FC Ringshausen, A Roux, MW Pletz, N Hämäläinen, T Welte, J Rademacher |
PloS one | 2013 |
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Burden and trends of hospitalisations associated with pulmonary non-tuberculous mycobacterial infections in Germany, 2005-2011
FC Ringshausen, RM Apel, FC Bange, A Roux, MW Pletz, J Rademacher, H Suhling, D Wagner, T Welte |
BMC Infectious Diseases | 2013 |
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Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world?
A Beceiro, M Tomás, G Bou |
Clinical microbiology reviews | 2013 |
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Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells
S Moriya, XF Che, S Komatsu, A Abe, T Kawaguchi, A Gotoh, M Inazu, A Tomoda, K Miyazawa |
International journal of oncology | 2013 |
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Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases
H Li, DH Liu, LL Chen, Q Zhao, YZ Yu, JJ Ding, LY Miao, YL Xiao, HR Cai, DP Zhang, YB Guo, CM Xie |
Antimicrobial agents and chemotherapy | 2013 |
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Cystic fibrosis: a mucosal immunodeficiency syndrome
TS Cohen, A Prince |
Nature Medicine | 2012 |
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Autophagy modulation as a potential therapeutic target for diverse diseases
DC Rubinsztein, P Codogno, B Levine |
Nature Reviews Drug Discovery | 2012 |
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Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics
HC Steel, AJ Theron, R Cockeran, R Anderson, C Feldman |
Mediators of Inflammation | 2012 |
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The emerging importance of autophagy in pulmonary diseases
K Mizumura, SM Cloonan, JA Haspel, AM Choi |
Chest | 2012 |
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4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C
GA Stewart, R Ridsdale, EP Martin, CL Na, Y Xu, K Mandapaka, TE Weaver |
American journal of respiratory cell and molecular biology | 2012 |
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Non-tuberculous mycobacteria in cystic fibrosis
UG Hill, RA Floto, CS Haworth |
Journal of the Royal Society of Medicine | 2012 |
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