Phenotypic diversity and genotypic flexibility of Burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs

Abstract

Chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. Tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. We carried out genomic and phenotypic analyses of 215 serially collected Burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range of epidemic lineages. Systematic phenotypic tests identified longitudinal bacterial series that manifested progressive changes in liquid media growth, motility, biofilm formation, and acute insect virulence, but not in mucoidy. The results suggest that distinct lineages follow distinct evolutionary trajectories during lung infection. Pan-genome analysis identified 10,110 homologous gene clusters present only in a subset of strains, including genes restricted to different molecular types. Our phylogenetic analysis based on 2148 orthologous gene clusters from all isolates is consistent with patient-specific clades. This suggests that initial colonization of patients was likely by individual strains, followed by subsequent diversification. Evidence of clonal lineages shared by some patients was observed, suggesting inter-patient transmission. We observed recurrent gene losses in multiple independent longitudinal series, including complete loss of Chromosome III and deletions on other chromosomes. Recurrently observed loss-of-function mutations were associated with decreases in motility and biofilm formation. Together, our study provides the first comprehensive genome-phenome analyses of B. cenocepacia infection in cystic fibrosis lungs and serves as a valuable resource for understanding the genomic and phenotypic underpinnings of bacterial evolution.

Epidemiology of E. coli in Cystic Fibrosis Airways Demonstrates the Capacity for Persistent Infection but Not Patient-Patient Transmission

“…Estimated substitution rates were consistent with those previously reported for E. coli and specifically the three shared STs (Reeves et al, 2011;Stoesser et al, 2016;Johnson et al, 2019) but were inconsistent with interpatient SNP distances such that one patient's isolates may have evolved directly from those of another. Further, the observation of tight phylogenetic clustering of individual patients' isolates with long branches between patients is consistent with the independent acquisition and subsequent clonal expansion of unique E. coli lineages in each patient -a phenomenon recently reported in studies of infection dynamics of other CF pathogens (Caballero et al, 2015;Lee et al, 2017). We did not observe any instances where one patient's E. coli diversity was completely contained within the diversity of another patient -an indicator of potential transmission noted in other transmission studies (Bryant et al, 2013).…”

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

“…Most of the SNPs were missense variants occurring in CDSs. As frequently observed during long-term within-host evolution of clones [11, 34, 35], a genome reduction was evidenced for the 4 clones with late isolates having reduced genome size (with a genetic loss ranging from 10 to 81 kb) compared to early isolates ( S1 Table ). Large deletions were plasmids or prophage regions lost during chronic infection ( S2 Table ).…”

Host adaptations in thefixLJpathway of theBurkholderia cepaciacomplex increase virulence

“…45,46 Less is known about phenotypic changes that occur during chronic BCC infection, and most prior work has focused on B. cenocepacia. 48 The findings from this study demonstrate a novel way BCC adapt to the host by making the bacteria more pathogenic at the cost of being less able to survive within the environment.…”