Hyperglycemia increases the severity ofStaphylococcus aureusosteomyelitis and influences bacterial genes required for survival in bone

Abstract

ABSTRACTHyperglycemia, or elevated blood glucose, renders individuals more prone to developing severeStaphylococcus aureusinfections.S. aureusis the most common etiological agent of musculoskeletal infection, which is a common manifestation of disease in hyperglycemic patients. However, the mechanisms by whichS. aureuscauses severe musculoskeletal infection during hyperglycemia are incompletely characterized. To examine the influence of hyperglycemia onS. aureusvirulence during invasive infection, we used a murine model of osteomyelitis and induced hyperglycemia with streptozotocin. We discovered that hyperglycemic mice exhibited increased bacterial burdens in bone and enhanced dissemination compared to control mice. Furthermore, infected hyperglycemic mice sustained increased bone destruction relative to euglycemic controls, suggesting that hyperglycemia exacerbates infection-associated bone loss. To identify genes contributing toS. aureuspathogenesis during osteomyelitis in hyperglycemic animals relative to euglycemic controls, we used transposon sequencing (TnSeq). We identified 71 genes uniquely essential forS. aureussurvival in osteomyelitis in hyperglycemic mice and another 61 mutants with compromised fitness. Among the genes essential forS. aureussurvival in hyperglycemic mice was superoxide dismutase A (sodA), one of twoS. aureussuperoxide dismutases involved in detoxifying reactive oxygen species (ROS). We determined that asodAmutant exhibits attenuated growthin vitroin high glucose andin vivoduring osteomyelitis in hyperglycemic mice. SodA therefore serves an important role during growth in high glucose and promotesS. aureussurvival in bone. Collectively, these studies demonstrate that hyperglycemia increases the severity of osteomyelitis and identify genes contributing toS. aureussurvival during hyperglycemic infection.