Mycobacterium abscessus Clearance by Neutrophils Is Independent of Autophagy

• Published in: Infection and immunity 2020-07, Vol.88 (8)
• Main Authors: Pohl, Kerstin, Grimm, Xue A, Caceres, Silvia M, Poch, Katie R, Rysavy, Noel, Saavedra, Milene, Nick, Jerry A, Malcolm, Kenneth C
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; Anti-Bacterial Agents - pharmacology; Autophagy - drug effects; Autophagy - immunology; Azithromycin - pharmacology; Case-Control Studies; Chemokine CCL4 - genetics; Chemokine CCL4 - immunology; Chloroquine - pharmacology; Cystic Fibrosis - genetics; Cystic Fibrosis - immunology; Cystic Fibrosis - microbiology; Cystic Fibrosis - pathology; Gene Expression Regulation; Host Response and Inflammation; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunosuppressive Agents - pharmacology; Interleukin-8 - genetics; Interleukin-8 - immunology; Mycobacterium abscessus - drug effects; Mycobacterium abscessus - genetics; Mycobacterium abscessus - immunology; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - microbiology; Phagocytosis - drug effects; Primary Cell Culture; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; Signal Transduction; Sirolimus - pharmacology; Wortmannin - pharmacology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00024-20

, a rapidly growing nontuberculous mycobacterium, is increasingly prevalent in chronic lung disease, including cystic fibrosis, and infections are characterized by neutrophil-dominated environments. However, mechanisms of immune control are poorly understood. Azithromycin, a macrolide antibiotic with immunomodulatory effects, is used to treat infections. Recently, inhibition of macrophage bactericidal autophagy was described for azithromycin, which could be detrimental to the host. Therefore, we explored the role of autophagy in mycobactericidal neutrophils. Azithromycin did not affect -induced neutrophil reactive oxygen species formation, phagocytosis, or cytokine secretion, and neutrophils treated with azithromycin killed equally as well as untreated neutrophils from either healthy or cystic fibrosis subjects. One clinical isolate was killed more effectively in azithromycin-treated neutrophils, suggesting that pathogen-specific factors may interact with an azithromycin-sensitive pathway. Chloroquine and rapamycin, an inhibitor and an activator of autophagy, respectively, also failed to affect mycobactericidal activity, suggesting that autophagy was not involved. However, wortmannin, an inhibitor of intracellular trafficking, inhibited mycobactericidal activity, but as a result of inhibiting phagocytosis. The effects of these autophagy-modifying agents and azithromycin in neutrophils from healthy subjects were similar between the smooth and rough morphotypes of However, in cystic fibrosis neutrophils, wortmannin inhibited killing of a rough clinical isolate and not a smooth isolate, suggesting that unique host-pathogen interactions exist in cystic fibrosis. These studies increase our understanding of virulence and of neutrophil mycobactericidal mechanisms. Insight into the immune control of may provide novel targets of therapy.