Browsing by Subject "SaeRS"

Now showing 1 - 3 of 3
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    Regulation of Bacterial Two-Component Systems by Cardiolipin
    (American Society for Microbiology, 2023) Yeo, Won-Sik; Dyzenhaus, Sophie; Torres, Victor J.; Brinsmade, Shaun R.; Bae, Taeok; Microbiology and Immunology, School of Medicine
    The regulation of membrane protein activity for cellular functions is critically dependent on the composition of phospholipid membranes. Cardiolipin, a unique phospholipid found in bacterial membranes and mitochondrial membranes of eukaryotes, plays a crucial role in stabilizing membrane proteins and maintaining their function. In the human pathogen Staphylococcus aureus, the SaeRS two-component system (TCS) controls the expression of key virulence factors essential for the bacterium’s virulence. The SaeS sensor kinase activates the SaeR response regulator via phosphoryl transfer to bind its gene target promoters. In this study, we report that cardiolipin is critical for sustaining the full activity of SaeRS and other TCSs in S. aureus. The sensor kinase protein SaeS binds directly to cardiolipin and phosphatidylglycerol, enabling SaeS activity. Elimination of cardiolipin from the membrane reduces SaeS kinase activity, indicating that bacterial cardiolipin is necessary for modulating the kinase activities of SaeS and other sensor kinases during infection. Moreover, the deletion of cardiolipin synthase genes cls1 and cls2 leads to reduced cytotoxicity to human neutrophils and lower virulence in a mouse model of infection. These findings suggest a model where cardiolipin modulates the kinase activity of SaeS and other sensor kinases after infection to adapt to the hostile environment of the host and expand our knowledge of how phospholipids contribute to membrane protein function.
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    Regulation of the Sae Two-Component System by Branched- Chain Fatty Acids in Staphylococcus aureus
    (American Society for Microbiology, 2022) Pendleton, Augustus; Yeo, Won-Sik; Alqahtani, Shahad; DiMaggio, Dennis A., Jr.; Stone, Carl J.; Li, Zhaotao; Singh, Vineet K.; Montgomery, Christopher P.; Bae, Taeok; Brinsmade, Shaun R.; Microbiology and Immunology, School of Medicine
    Staphylococcus aureus is a ubiquitous Gram-positive bacterium and an opportunistic human pathogen. S. aureus pathogenesis relies on a complex network of regulatory factors that adjust gene expression. Two important factors in this network are CodY, a repressor protein responsive to nutrient availability, and the SaeRS two-component system (TCS), which responds to neutrophil-produced factors. Our previous work revealed that CodY regulates the secretion of many toxins indirectly via Sae through an unknown mechanism. We report that disruption of codY results in increased levels of phosphorylated SaeR (SaeR~P) and that codY mutant cell membranes contain a higher percentage of branched-chain fatty acids (BCFAs) than do wild-type membranes, prompting us to hypothesize that changes to membrane composition modulate the activity of the SaeS sensor kinase. Disrupting the lpdA gene encoding dihydrolipoyl dehydrogenase, which is critical for BCFA synthesis, significantly reduced the abundance of SaeR, phosphorylated SaeR, and BCFAs in the membrane, resulting in reduced toxin production and attenuated virulence. Lower SaeR levels could be explained in part by reduced stability. Sae activity in the lpdA mutant could be complemented genetically and chemically with exogenous short- or full-length BCFAs. Intriguingly, lack of lpdA also alters the activity of other TCSs, suggesting a specific BCFA requirement managing the basal activity of multiple TCSs. These results reveal a novel method of posttranscriptional virulence regulation via BCFA synthesis, potentially linking CodY activity to multiple virulence regulators in S. aureus.
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    Virulence adaption to environment promotes the age-dependent nasal colonization of Staphylococcus aureus
    (Taylor & Francis, 2022) Zhao, Na; Cheng, Danhong; Yang, Ziyu; Liu, Yao; Wang, Yanan; Jian, Ying; Wang, Hua; Li, Min; Bae, Taeok; Liu, Qian; Microbiology and Immunology, School of Medicine
    Staphylococcus aureus is an important human commensal bacteria colonizing the human body, especially the nasal cavity. The nasal carriage can be a source of S. aureus bacteremia. However, the bacterial factors contributing to nasal colonization are not completely understood. By analysing S. aureus strains from the nasal cavity of the children, young adults, and seniors, we found that the low activity of the SaeRS two-component system (TCS) is an important determinant for S. aureus to colonize in seniors. The senior group isolates of S. aureus showed a rather distinct sequence type composition as compared with other age group isolates. The senior group isolates showed not only a lower gene carriage of enterotoxins a, c, and q but also lower hemolytic activity against human red blood cells. Of regulators affecting hemolysin production (i.e. agr, saeRS, rot, rsp, and sarS), only the SaeRS TCS showed an age-dependent decrease of activity. The decreased virulence and better colonization ability of the senior group isolates of S. aureus were confirmed in the mouse model. The senior group isolates showed the lowest survival and the best adhesion and colonizing ability. Also, the senior nasal secretions supported S. aureus survival better than the child and young adult nasal secretions. These results indicated that the senior nasal cavity favours colonization of S. aureus with higher adhesion and lower virulence, to which the reduced SaeRS TCS activity contributes. Taken together, our results illustrate an example of bacterial adaptation to the changing host environment.