Mycobacterium abscessus Glycopeptidolipids mask underlying cell wall phosphatidyl-myo-inositol mannosides blocking induction of human macrophage TNF-alpha by preventing interaction with TLR2.
Mycobacterium abscessus causes disease in patients with structural abnormalities of the lung, and it is an emerging pathogen in patients with cystic fibrosis. Colonization of the airways by nontuberculous mycobacteria is a harbinger of invasive lung disease. Colonization is facilitated by biofilm formation, with M. abscessus glycopeptidolipids playing an important role. M. abscessus can transition between a noninvasive, biofilm-forming, smooth colony phenotype that expresses glycopeptidolipid, and an invasive rough colony phenotype that expresses minimal amounts of glycopeptidolipid and is unable to form biofilms. The ability of this pathogen to transition between these phenotypes may have particular relevance to lung infection in cystic fibrosis patients since the altered pulmonary physiology of these patients makes them particularly susceptible to colonization by biofilm-forming bacteria. In this study we demonstrate that rough variants of M. abscessus stimulate the human macrophage innate immune response through TLR2, while smooth variants do not. Temperature-dependent loss or physical removal of glycopeptidolipid from the cell wall of one of the smooth variants leads to TLR2 stimulation. This response is stimulated in part through phosphatidyl-myo-inositol mannosides that are present in the cell wall of both rough and smooth variants. Mannose-binding lectins bind to rough variants, but lectin binding to an isogenic smooth variant is markedly reduced. This suggests that glycopeptidolipid in the outermost portion of the M. abscessus cell wall masks underlying cell wall lipids involved in stimulating the innate immune response, thereby facilitating colonization. Conversely spontaneous "unmasking" of cell wall lipids may promote airway inflammation.
Rhoades
Elizabeth R
ER
Cornell Nanoscale Science and Technology Facility, Cornell University, Ithaca, NY 14853, USA.
Archambault
Angela S
AS
Greendyke
Rebecca
R
Hsu
Fong-Fu
FF
Streeter
Cassandra
C
Byrd
Thomas F
TF
D018441:Biofilms; D002473:Cell Wall / Q000737:chemistry; D003550:Cystic Fibrosis / Q000276:immunology; D006017:Glycolipids / Q000502:physiology*; D006020:Glycopeptides / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000378:metabolism*; D009161:Mycobacterium / Q000166:cytology / Q000472:pathogenicity*; D009164:Mycobacterium Infections; D010716:Phosphatidylinositols; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D006017:Glycolipids; D006020:Glycopeptides; D010716:Phosphatidylinositols; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C010762:peptidoglycolipids; C034154:phosphatidylinositol mannoside