Genomic Analyses of Longitudinal Mycobacterium abscessus Isolates in a Multicenter Cohort Reveal Parallel Signatures of In-Host Adaptation

Abstract

Background Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex (MAB) is one of the major NTM lung pathogens which disproportionately colonize and infect the lungs of individuals with cystic fibrosis (CF). MAB infection can persist for years, and antimicrobial treatment is frequently ineffective. Methods We sequence the genomes of 175 isolates longitudinally collected from 30 patients with MAB lung infection. We contextualize our cohort amidst the broader MAB phylogeny and investigate genes undergoing parallel adaptation across patients. Finally, we test the phenotypic consequences of parallel mutations by conducting antimicrobial resistance and mercury resistance assays. Results We identify highly related isolate pairs across hospital centers with low likelihood of transmission. We further annotate non-random parallel mutations in 22 genes and demonstrate altered macrolide susceptibility co-occurring with a nonsynonymous whiB1 mutation. Finally, we highlight a 23 kb mercury resistance plasmid whose loss during chronic infection confers phenotypic susceptibility to organic and non-organic mercury compounds. Conclusions We characterize parallel genomic processes through which MAB is adapting to promote survival within the host. The within-lineage polymorphisms we observe have phenotypic effects, potentially benefiting fitness in the host at the putative detriment of environmental survival.