Abstract
The success of Staphylococcus aureus, as both a human and animal pathogen, stems from its ability to rapidly adapt to a wide spectrum of environmental conditions. Two-component systems (TCSs) play a crucial role in this process. Here, we describe a novel staphylococcal virulence factor, SpdC, an Abi-domain protein, involved in signal sensing and/or transduction. We have uncovered a functional link between the WalKR essential TCS and the SpdC Abi membrane protein. Expression of spdC is positively regulated by the WalKR system and, in turn, SpdC negatively controls WalKR regulon genes, effectively constituting a negative feedback loop. The WalKR system is mainly involved in controlling cell wall metabolism through regulation of autolysin production. We have shown that SpdC inhibits the WalKR-dependent synthesis of four peptidoglycan hydrolases, SceD, SsaA, LytM and AtlA, as well as impacting S. aureus resistance towards lysostaphin and cell wall antibiotics such as oxacillin and tunicamycin. We have also shown that SpdC is required for S. aureus biofilm formation and virulence in a murine septicemia model. Using protein-protein interactions in E. coli as well as subcellular localization in S. aureus, we showed that SpdC and the WalK kinase are both localized at the division septum and that the two proteins interact. In addition to WalK, our results indicate that SpdC also interacts with nine other S. aureus histidine kinases, suggesting that this membrane protein may act as a global regulator of TCS activity. Indeed, using RNA-Seq analysis, we showed that SpdC controls the expression of approximately one hundred genes in S. aureus, many of which belong to TCS regulons.
Highlights
Two-component systems (TCSs) are composed of a histidine kinase, usually membranebound and acting as an environmental sensor, which phosphorylates a coupled response regulator, often controlling gene transcription
S. aureus adapts to its environment by adjusting its genetic expression through sensing and regulatory systems
Among the 16 TCSs encoded by the S. aureus genome [3], the SaeSR, AgrCA, and WalKR systems are important for controlling virulence and innate immune evasion factors [4,5,6,7,8]
Summary
Two-component systems (TCSs) are composed of a histidine kinase, usually membranebound and acting as an environmental sensor, which phosphorylates a coupled response regulator, often controlling gene transcription. These systems have been extensively studied and play an essential role in bacterial adaptation to the environment, the signal(s) to which they respond and additional factors positively or negatively controlling their activities remain mostly unknown. S. aureus is a commensal bacterium, colonizing approximately half the human population asymptomatically, essentially within the anterior nares [2]. In addition to its considerable arsenal of virulence factors, S. aureus must rapidly adapt to environmental conditions encountered during host colonization. Among the 16 TCSs encoded by the S. aureus genome [3], the SaeSR, AgrCA, and WalKR systems are important for controlling virulence and innate immune evasion factors [4,5,6,7,8]
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