High-Resolution Transcriptomic Analysis of the Adaptive Response of Staphylococcus aureus during Acute and Chronic Phases of Osteomyelitis
ABSTRACTOsteomyelitis is a difficult-to-eradicate bone infection typically caused byStaphylococcus aureus. In this study, we investigated thein vivotranscriptional adaptation ofS. aureusduring bone infection. To this end, we determined the transcriptome ofS. aureusduring the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed byS. aureusduring acute or chronicin vivoinfection than underin vitrogrowth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level,sarAand -RandsaeRand -Sas well as the small RNA RsaC were predominantly expressed byS. aureusduringin vivoinfection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed byS. aureusduring the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of thesein vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis,S. aureusinduced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however,S. aureusswitched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies ofS. aureusduring chronic infection could lead to more effective treatments.IMPORTANCEThe key to the survival success of pathogens during an infection is their capacity to rapidly adjust to the host environment and to evade the host defenses. Understanding how a pathogen redirects and fine-tunes its gene expression in response to the challenges of infection is central to the development of more efficient anti-infective therapies. Osteomyelitis is a debilitating infection of the bone predominantly caused byS. aureus. In this study, we evaluated the transcriptional response ofS. aureusduring bone infection. Our results indicate thatS. aureusreprograms its genetic repertoire during the acute phase of infection to adapt to nutrient availability and to replicate within the host. During the chronic phase,S. aureusupregulates a survival genetic program activated in response to nutrient starvation. Thus, we have uncovered key survival pathways ofS. aureusduring acute and chronic osteomyelitis that can be used as therapeutic targets.