Adaptive evolution of Staphylococcus aureus during chronic endobronchial infection of a cystic fibrosis patient

Abstract

The molecular adaptation of Staphylococcus aureus to its host during chronic infection is not well understood. Comparative genome sequencing of 3 S. aureus isolates obtained sequentially over 26 months from the airways of a cystic fibrosis patient, revealed variation in phage content, and genetic polymorphisms in genes which influence antibiotic resistance, and global regulation of virulence. The majority of polymorphisms were isolate-specific suggesting the existence of an heterogeneous infecting population that evolved from a single infecting strain of S. aureus. The genetic variation identified correlated with differences in growth rate, hemolytic activity, and antibiotic sensitivity, implying a profound effect on the ecology of S. aureus. In particular, a high frequency of mutations in loci associated with the alternate transcription factor SigB, were observed. The identification of genes under diversifying selection during long-term infection may inform the design of novel therapeutics for the control of refractory chronic infections.

Figure 1. Genetic and phenotypic heterogeneity among sequential S. aureus CF isolates.

(A) Maximum likelihood phylogeny based on core genome point mutations for the 3 CF isolates in comparison to 5 additional CC30 isolates. MRSA252 is representative of hospital associated epidemic ST36 strains , BTN1260 and c101 are methicillin sensitive (MSSA) ST30 isolates from a global collection , 00_3031_G and 07_1973_G are a community associated MSSA and a hospital associated MRSA from Scotland, respectively (unpublished data). Scale represents substitutions per site. Growth curves in threonine-depleted CDM for (B) smaller (S) and larger (L) colony variants of ED83, (C) ED84 and (D) smaller (S) and larger (L) colony variants of ED86. Hemolytic activity on sheep erythrocytes for (E) colony variants of ED83, (F) ED84 and (G) colony variants of ED86.