Genetic diversification of persistent <i>Mycobacterium abscessus</i> within cystic fibrosis patients

<i>Mycobacterium</i> (<i>M</i>.) <i>abscessus</i> infections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight on <i>M. abscessus</i> genomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patient <i>M. abscessus</i>. Eleven of the 42 CF patients were infected with <i>M. abscessus</i>. Five of these 11 patients were infected with global human-transmissible <i>M. abscessus</i> cluster strains. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence of <i>M. abscessus</i> transmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over 4.5 years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from the <i>embABC</i> (arabinosyltransferase) operon, <i>betA</i> (glucose-methanol-choline oxidoreductase) and <i>cho</i>D (cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy of <i>M. abscessus</i> populations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies against <i>M. abscessus</i> infections are explored.