Abstract
To date, genes identified and transcriptionally regulated by the AirSR TCS have been involved in energy production and cellular homeostasis of the staphylococcal cell. It is well accepted that the state of cellular metabolism impacts the expression of virulence factors in Staphylococcus aureus. For this reason, we conducted experiments to determine if the AirSR TCS contributes to the pathogenesis of S. aureus using an antisense RNA interference technology, an inducible overexpression system, and gene deletions. Depletion of AirSR by antisense RNA expression or deletion of the genes, results in significant decrease in bacterial survival in human blood. Conversely, overexpression of AirR significantly promotes survival of S. aureus in blood. AirR promotes the secretion of virulence factors that inhibits opsonin-based phagocytosis. This enhanced survival is partially linked to the transcriptional regulation of the sspABC operon, encoding V8 protease (SspA), staphopain B (SspB) and staphostatin B (SspC). SspA and SspB are known virulence factors which proteolytically digest opsonins and inhibit killing of S. aureus by professional phagocytes. This is the first evidence linking the AirSR TCS to pathogenesis of S. aureus.
Highlights
Staphylococcus aureus accounts for approximately 20% of bloodstream infections in the U.S (Wisplinghoff et al, 2004)
AirSR Contributes to the Survival of S. aureus in Human Blood The AirSR TCS is essential for growth in S. aureus WCUH29 (Sun et al, 2005), and it is important to validate the in vivo essentiality of any gene as some genes found to be essential in vitro may not be essential in vivo (Gandotra et al, 2007; Brinster et al, 2009)
An equal number of colony forming units (CFUs) per strain were inoculated into a defined volume of freshly isolated venous blood and depletion of AirSR by induction of airSR antisense RNA with ATc (Sun et al, 2005) resulted in a significantly decreased percentage of ATc induced JSAS909 CFUs surviving in the first half hour of incubation in human blood compared to the non-induced inoculum (Figure 1A, 18% vs. 40%)
Summary
Staphylococcus aureus accounts for approximately 20% of bloodstream infections in the U.S (Wisplinghoff et al, 2004). The bacteria gain access to the bloodstream commonly from the result of puncture wounds of the skin (Saravolatz et al, 1982; Control Centers for Disease Control and Prevention [CDC], 2003; Begier et al, 2004), surgical site infections, or insertion of central venous lines and catheters (Maki et al, 1997; Wisplinghoff et al, 2004). Once S. aureus enters the bloodstream, the bacteria have the ability to enter almost any site of the human body (Gordon and Lowy, 2008). S. aureus bloodstream infections often lead to septic shock and endocarditis (Lowy, 1998). Septic shock and endocarditis accounted for an additional 10% of invasive infections (Klevens et al, 2007)
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