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

• Published in: The Journal of infectious diseases Vol. 228; no. 3; pp. 321 - 331
• Main Authors: Choi, JooHee, Keen, Eric C, Wallace, Meghan A, Fishbein, Skye, Prusa, Jerome, Zimbric, Madsen, Mejia-Chew, Carlos R, Mehta, Shail B, Bailey, Thomas C, Caverly, Lindsay J, Burnham, Carey-Ann D, Dantas, Gautam
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 11.08.2023
• Subjects: Adaptation; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial agents; Antimicrobial resistance; Bronchopulmonary infection; Chronic infection; Clarithromycin; Cystic fibrosis; Genomic analysis; Genomics; Host Adaptation; Humans; Infections; Major; Mercury compounds; Mutation; Mycobacterium abscessus; Mycobacterium abscessus - genetics; Mycobacterium Infections, Nontuberculous - microbiology; Patients; Phylogeny; Survival; nontuberculous mycobacteria; in-host adaptation; comparative genomics; complex; Mycobacterium abscessus complex
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiad187

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