Abstract
Genetic variation among bacterial strains can contribute to heterogeneity in the severity of chronic inflammatory diseases 1,2, but the degree of variation created by de novo mutation during colonization is not well understood. The inflamed skin of people with atopic dermatitis (AD) is frequently colonized with Staphylococcus aureus, an opportunistic pathogen associated with both asymptomatic colonization of nasal passages and invasive disease 3–6. While genetic risk and barrier disruption are critical to AD initiation 7,8, S. aureus colonization is thought to worsen disease severity by promoting skin damage9,1,4,5,10. Here we show, from tracking 23 children treated for AD over 9 months, that S. aureus adapts via de novo mutations during colonization. Patients’ S. aureus populations are typically dominated by a single lineage, with infrequent invasion by distant lineages. Variants emerge within each lineage with mutation accumulation rates similar to S. aureus in other contexts. Some of these variants replace their ancestors across the body within months, with signatures of adaptive, rather than neutral, forces. Most strikingly, the capsule synthesis gene capD obtained four parallel mutations within one patient and was involved in mutational sweeps in multiple patients. We confirm that selection for capD negativity is common in AD, but not in other contexts, via reanalysis of public S. aureus genomes from 276 people. Our finding of disease-specific selection raises the possibility that adaptation of pathobionts during colonization prolongs the positive feedback cycle of inflammation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
- To emphasize that we have evidence of S. aureus sweeps in 20 subjects, we now better highlight the across-subject tMRCA analysis by splitting the previous Figure 2 into new Figures 2 and 3. We have accordingly restructered the section 'S. aureus mutants sweep across the body' to mention this analysis early in the text. Notably, this analysis was performed on the earliest possible timepoint for each subject (80% from first visit), and therefore reflects sweeps that happened before the treatment in our study. - We have updated the description of the clinical interventions. In particular, we note that patients applied topical corticosteroids at rates proportional to disease severity and in accordance with best practice and list specific usages in Supplementary Table 1. - We provide evidence that sweeps in common in other subjects via re-analysis of single-timepoint S. aureus diversity in 8 subjects from a prior study in new Extended Data Figure 4.