RT Journal Article
SR Electronic
T1 The microbial basis of impaired wound healing: differential roles for pathogens, “bystanders”, and strain-level diversification in clinical outcomes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 427567
DO 10.1101/427567
A1 Lindsay Kalan
A1 Jacquelyn S. Meisel
A1 Michael A. Loesche
A1 Joseph Horwinski
A1 Ioana Soaita
A1 Xiaoxuan Chen
A1 Sue E. Gardner
A1 Elizabeth A. Grice
YR 2018
UL http://biorxiv.org/content/early/2018/09/27/427567.abstract
AB Chronic, non-healing wounds are a major complication of diabetes associated with high morbidity and health care expenditures estimated at $9-13 billion annually in the US. Though microbial infection and critical colonization is hypothesized to impair healing and contribute to severe outcomes such as amputation, antimicrobial therapy is inefficacious and the role of microbes in tissue repair, regeneration, and healing remains unclear. Here, in a longitudinal prospective cohort study of 100 subjects with non-infected neuropathic diabetic foot ulcer (DFU), we performed metagenomic shotgun sequencing to elucidate microbial temporal dynamics at strain-level resolution, to investigate pathogenicity and virulence of the DFU microbiome with respect to outcomes, and to determine the influence of therapeutic intervention on the DFU microbiota. Slow healing DFUs were associated with signatures of biofilm formation, host invasion, and virulence. Though antibiotic resistance was widespread at the genetic level, debridement, rather than antibiotic treatment, significantly shifted the DFU microbiome in patients with more favorable outcomes. Primary clinical isolates of S. aureus, C. striatum, and A. faecalis induced differential biological responses in keratinocytes and in a murine model of diabetic wound healing, with the S. aureus strain associated with non-healing wounds eliciting the most severe phenotype. Together these findings implicate strain-level diversification of the wound pathogen S. aureus in chronic wound outcomes, while revealing potential contributions from skin commensals and other previously underappreciated constituents of the wound microbiota.