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by Preventing Interaction with TLR21
,¶
* Cornell Nanoscale Science and Technology Facility, Cornell University, Ithaca, NY 14853;
The University of New Mexico School of Medicine, Albuquerque, NM 87131;
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110;
Department of Animal Science, Cornell University, Ithaca, NY 14853; and
¶ Department of Medicine, New Mexico Veterans Health Care System, Albuquerque, NM 87108
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Department of Veterans Affairs, the DeSouza Research Award from American Lung Association, and a grant from the Cystic Fibrosis Foundation (to T.F.B.).
2 Address correspondence and reprint requests to Dr. Thomas F. Byrd, Department of Medicine, New Mexico Veterans Health Care System,, Building T12A (151), 1501 San Pedro, SE, Albuquerque, NM 87108. E-mail address: tbyrd{at}salud.unm.edu
3 Abbreviations used in this paper: NTM, nontuberculous mycobacteria; GPL, glycopeptidolipid; PIM, phosphatidyl-myo-inositol mannoside; GNA, Galanthus nivalis agglutinin; TLC, thin layer chromatography; MDM, monocyte-derived macrophage; TDM, trehalose dimycolate; PG, phosphatidylglycerol; LM, lipomannan; LAM, lipoarabinomannan; MAC, Mycobacterium avium-intracellulare complex.
4 The online version of this article contains supplemental material.
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