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Crosby, HA, Schlievert, PM, Merriman, JA, King, JM, Salgado-Pabón, W and Horswill, AR (2016) The Staphylococcus aureus Global Regulator MgrA Modulates Clumping and Virulence by Controlling Surface Protein Expression. PLoS Pathog. 12:e1005604
Staphylococcus aureus is a human commensal and opportunistic pathogen that causes devastating infections in a wide range of locations within the body. One of the defining characteristics of S. aureus is its ability to form clumps in the presence of soluble fibrinogen, which likely has a protective benefit and facilitates adhesion to host tissue. We have previously shown that the ArlRS two-component regulatory system controls clumping, in part by repressing production of the large surface protein Ebh. In this work we show that ArlRS does not directly regulate Ebh, but instead ArlRS activates expression of the global regulator MgrA. Strains lacking mgrA fail to clump in the presence of fibrinogen, and clumping can be restored to an arlRS mutant by overexpressing either arlRS or mgrA, indicating that ArlRS and MgrA constitute a regulatory pathway. We used RNA-seq to show that MgrA represses ebh, as well as seven cell wall-associated proteins (SraP, Spa, FnbB, SasG, SasC, FmtB, and SdrD). EMSA analysis showed that MgrA directly represses expression of ebh and sraP. Clumping can be restored to an mgrA mutant by deleting the genes for Ebh, SraP and SasG, suggesting that increased expression of these proteins blocks clumping by steric hindrance. We show that mgrA mutants are less virulent in a rabbit model of endocarditis, and virulence can be partially restored by deleting the genes for the surface proteins ebh, sraP, and sasG. While mgrA mutants are unable to clump, they are known to have enhanced biofilm capacity. We demonstrate that this increase in biofilm formation is partially due to up-regulation of SasG, a surface protein known to promote intercellular interactions. These results confirm that ArlRS and MgrA constitute a regulatory cascade, and that they control expression of a number of genes important for virulence, including those for eight large surface proteins.
|Gene product||Qualifier||GO Term||Evidence Code||with/from||Aspect||Extension||Notes||Status|
|GO:0043708: cell adhesion involved in biofilm formation||
Figure 1: MgrA is needed for clumping in S. aureus strain RN4220. Wild type, a deleted mutant and an exogenous expressed mutant were incubated in plasma and fibrinogen. The images show clumping in the wild type and mgrA expressed mutant.
Figure 2: ebh is a surface protein that blocks clumping. It is repressed by mgrA (Fig 5d and 5a). Other proteins are known to block clumping and are impacted by mgrA, one being sasG and sraP (fig 8+9)
Figure 11: Biofilm formation increased in mutants lacking mgrA, with the increase in ebh. This is due to the up-regulation of the protein sasG, which is one of the proteins up-regulated with ebh as a result of the deletion of mgrA. This protein increases intercellular adhesion, meaning clumping decreases but biofilm formation is enhanced (fig 12)
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