title: Pathogenic nontuberculous mycobacteria resist and inactivate cathelicidin: implication of a novel role for polar mycobacterial lipids.
abstract: Nontuberculous mycobacteria (NTM) are a large group of environmental organisms with worldwide distribution, but only a relatively few are known to be pathogenic. Chronic, debilitating lung disease is the most common manifestation of NTM infection, which is often refractory to treatment. The incidence and prevalence of NTM lung disease are increasing in the United States and in many parts of the world. Hence, a more complete understanding of NTM pathogenesis will provide the foundation to develop innovative approaches to treat this recalcitrant disease. Herein, we demonstrate that several species of NTM show broad resistance to the antimicrobial peptide, cathelicidin (LL-37). Resistance to LL-37 was not significantly different between M. avium that contain serovar-specific glycopeptidolipid (GPL, M. aviumssGPL) and M. avium that do not (M. aviumΔssGPL). Similarly, M. abscessus containing non-specific GPL (M. abscessusnsGPL(+)) or lacking nsGPL (M. abscessusnsGPL(-)) remained equally resistant to LL-37. These findings would support the notion that GPL are not the components responsible for NTM resistance to LL-37. Unexpectedly, the growth of M. abscessusnsGPL(-) increased with LL-37 or scrambled LL-37 peptide in a dose-dependent fashion. We also discovered that LL-37 exposed to NTM had reduced antimicrobial activity, and initial work indicates that this is likely due to inactivation of LL-37 by lipid component(s) of the NTM cell envelope. We conclude that pathogenic NTM resist and inactivate LL-37. The mechanism by which NTM circumvent the antimicrobial activity of LL-37 remains to be determined.
authors.affiliation: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; National Jewish Health, Denver, Colorado, United States of America; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Honda
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Hess
authors.affiliation: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; National Jewish Health, Denver, Colorado, United States of America.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Malcolm
authors.affiliation: National Jewish Health, Denver, Colorado, United States of America; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Alida R
authors.initials: AR
authors.lastname: Ovrutsky
authors.affiliation: National Jewish Health, Denver, Colorado, United States of America; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Biology, Indiana University of Pennsylvania, Indiana, Pennsylvania, United States of America.
authors.forename: Vida R
authors.initials: VR
authors.lastname: Irani
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dobos
authors.affiliation: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America; National Jewish Health, Denver, Colorado, United States of America; Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.affiliation: Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Flores
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids; D008826:Microbial Sensitivity Tests; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D008055:Lipids; D054804:Cathelicidins