Mycobacterium abscessus-Induced Granuloma Formation Is Strictly Dependent on TNF Signaling and Neutrophil Trafficking.
Mycobacterium abscessus is considered the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. Infections with M. abscessus are increasingly found in patients with chronic lung diseases, especially cystic fibrosis, and are often refractory to antibiotic therapy. M. abscessus has two morphotypes with distinct effects on host cells and biological responses. The smooth (S) variant is recognized as the initial airway colonizer while the rough (R) is known to be a potent inflammatory inducer associated with invasive disease, but the underlying immunopathological mechanisms of the infection remain unsolved. We conducted a comparative stepwise dissection of the inflammatory response in S and R pathogenesis by monitoring infected transparent zebrafish embryos. Loss of TNFR1 function resulted in increased mortality with both variants, and was associated with unrestricted intramacrophage bacterial growth and decreased bactericidal activity. The use of transgenic zebrafish lines harboring fluorescent macrophages and neutrophils revealed that neutrophils, like macrophages, interact with M. abscessus at the initial infection sites. Impaired TNF signaling disrupted the IL8-dependent neutrophil mobilization, and the defect in neutrophil trafficking led to the formation of aberrant granulomas, extensive mycobacterial cording, unrestricted bacterial growth and subsequent larval death. Our findings emphasize the central role of neutrophils for the establishment and maintenance of the protective M. abscessus granulomas. These results also suggest that the TNF/IL8 inflammatory axis is necessary for protective immunity against M. abscessus and may be of clinical relevance to explain why immunosuppressive TNF therapy leads to the exacerbation of M. abscessus infections.
Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, FR3689, CNRS, Univ Montpellier, Montpellier, France.
Audrey
A
Bernut
DIMNP, CNRS, Univ Montpellier, Montpellier, France.
Mai
M
Nguyen-Chi
Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, FR3689, CNRS, Univ Montpellier, Montpellier, France.
Iman
http://orcid.org/0000-0001-6251-745X
I
Halloum
UMR1173, INSERM, Université de Versailles St Quentin, Montigny le Bretonneux, France.
Jean-Louis
http://orcid.org/0000-0003-2347-6418
JL
Herrmann
DIMNP, CNRS, Univ Montpellier, Montpellier, France.
Georges
http://orcid.org/0000-0002-6591-7894
G
Lutfalla
Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, FR3689, CNRS, Univ Montpellier, Montpellier, France.|INSERM, CPBS, Montpellier, France.
Laurent
L
Kremer
D000818:Animals; D030801:Animals, Genetically Modified; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D006099:Granuloma / Q000276:immunology* / Q000473:pathology; D008853:Microscopy; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D009170:Nontuberculous Mycobacteria / Q000276:immunology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015027:Zebrafish
D014409:Tumor Necrosis Factor-alpha