The Skeletal Environment and Comorbid Hyperglycemia Influence Staphylococcus aureus Virulence During Osteomyelitis

Abstract

Staphylococcus aureus is a leading cause of bacterial infections and can infect nearly every organ of the human body. One common manifestation of S. aureus disease is invasive bone infection, or osteomyelitis. Osteomyelitis is one of the most difficult-to-treat infections, often necessitating prolonged antibiotic treatment and surgical interventions. The treatment recalcitrance associated with osteomyelitis in addition to prior observations suggesting S. aureus is capable of surviving in multiple tissues and abscess structures led us to hypothesize that unique genes are required for staphylococcal survival within the bone. To identify genes involved in enhancing S. aureus virulence in the bone, we conducted a transposon sequencing (TnSeq) analysis using a murine osteomyelitis model. We identified a putative amino acid transporter, PheP, implicated in S. aureus survival in both intravenous and osteomyelitis infection. While healthy individuals are at a risk for developing S. aureus infections, individuals with comorbid hyperglycemia, or elevated blood glucose, experience greater incidence of infection and receive poorer prognoses. We therefore studied the effects of hyperglycemia on S. aureus osteomyelitis infection dynamics. We discovered that streptozotocin-treated hyperglycemic mice exhibited greater S. aureus burdens within infected femurs, increased dissemination, and enhanced infection-induced bone loss compared to vehicle-treated euglycemic infected mice. To identify genes that facilitate S. aureus survival in bone during hyperglycemia, we conducted TnSeq in hyperglycemic mice. We identified several characterized virulence genes essential for S. aureus survival in osteomyelitis during comorbid hyperglycemia including superoxide dismutase A (sodA). Collectively, these data characterize a putative S. aureus nutrient transporter required for invasive infection and reveal virulence genes that contribute to S. aureus survival in osteomyelitis infection during hyperglycemia.