Lipoarabinomannan modification as a source of phenotypic heterogeneity in host-adapted <i>Mycobacterium abscessus</i> isolates.

Abstract

<i>Mycobacterium abscessus</i> is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of <i>M. abscessus</i> to the human lung is <i>embC</i> which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived <i>embC</i> mutations on the physiology and virulence of <i>M. abscessus</i>, mutations were introduced in the isogenic background of <i>M. abscessus</i> ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection. We show that patient-derived mutational variations in EmbC result in an unexpectedly large number of changes in the physiology of <i>M. abscessus,</i> and its interactions with innate immune cells. Not only did the mutants produce previously unknown forms of LAM with a truncated arabinan domain and 3-linked oligomannoside chains, they also displayed significantly altered cording, sliding motility, and biofilm-forming capacities. The mutants further differed from wild-type <i>M. abscessus</i> in their ability to replicate and induce inflammatory responses in human monocyte-derived macrophages and epithelial cells. The fact that different <i>embC</i> mutations were associated with distinct physiologic and pathogenic outcomes indicates that structural alterations in LAM caused by nonsynonymous nucleotide polymorphisms in <i>embC</i> may be a rapid, one-step, way for <i>M. abscessus</i> to generate broad-spectrum diversity beneficial to survival within the heterogeneous and constantly evolving environment of the infected human airway.