Stiftung Tierärztliche Hochschule Hannover (TiHo)

Type I interferon induced by TLR2-TLR4-MyD88-TRIF-IRF3 controls Mycobacterium abscessus subsp. abscessus persistence in murine macrophages via nitric oxide

GND
1078982309
ORCID
0000-0003-4659-4441
Affiliation
Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Ruangkiattikul, Nanthapon;
Affiliation
Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Rys, Doris;
Affiliation
Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Abdissa, Ketema;
Affiliation
Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Rohde, Manfred;
ORCID
0000-0002-2225-7267
Affiliation
NG1 Microbial Genomics, Robert Koch Institute, Berlin, Germany.
Semmler, Torsten;
Affiliation
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between The Helmholtz Centre for Infection Research, Braunschweig, and The Hannover Medical School, Hannover, Germany.
Tegtmeyer, Pia-K.;
Affiliation
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between The Helmholtz Centre for Infection Research, Braunschweig, and The Hannover Medical School, Hannover, Germany.
Kalinke, Ulrich;
ORCID
0000-0003-3474-2857
Affiliation
Department of Pediatric Pneumonology and Immunology, Division of Cystic Fibrosis, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Schwarz, Carsten;
Affiliation
FG16 Mycotic and Parasitic Agents and Mycobacteria, Robert Koch Institute, Berlin, Germany.
Lewin, Astrid;
GND
1079298096
ORCID
0000-0002-0348-3090
Affiliation
Institute for Microbiology, University of Veterinary Medicine Hannover, Hannover, Germany. Electronic address: ralph.goethe@tiho-hannover.de.
Goethe, Ralph

Mycobacterium abscessus (MAB) is an emerging, rapidly growing non-tuberculous Mycobacterium causing therapy-resistant pulmonary disease especially in patients with cystic fibrosis (CF). Smooth and rough colony type MAB can be isolated from infected patients whereby rough colony type MAB are more often associated with severe disease. Disease severity is also associated with an alternated type I interferon (IFN-I) response of the MAB-infected patients. However the relevance of this response for the outcome of MAB infection is still unknown. In this study, we analyzed the IFNβ expression of murine macrophages infected with a MAB rough colony strain (MAB-R) isolated from a patient with progressive CF and compared it to macrophages infected with the MAB smooth colony type reference strain (MAB-S). We found that MAB-R infected macrophages expressed significantly more IFNβ mRNA and protein than MAB-S infected macrophages. Higher IFNβ induction by MAB-R was associated with higher TNF expression and intracellular killing while low IFNβ induction was associated with lower TNF expression and persistence of MAB-S. IFNβ induction was independent of the intracellular cGAS-STING recognition pathway. MAB appeared to be recognized extracellularly and induced IFNβ expression via TLR2-TLR4-MyD88-TRIF-IRF3 dependent pathways. By using macrophages lacking the IFN-I receptor we demonstrate that MAB induced IFN-I response essentially contributed to restricting MAB-R and MAB-S infections by activating macrophage Nos2 expression and nitric oxide production. Thus IFN-I seem to influence the intrinsic ability of macrophages to control MAB infections. As MAB persists over long time periods in susceptible patients, our findings suggest that virulence of MAB strains is promoted by an insufficient IFN-I response of the host.

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