The Staphylococcus aureus Global Regulator MgrA Modulates Clumping and Virulence by Controlling Surface Protein Expression.
The Staphylococcus aureus Global Regulator MgrA Modulates Clumping and Virulence by Controlling Surface Protein Expression.
复制标题
金黄色葡萄球菌全球调节剂MGRA通过控制表面蛋白表达来调节结块和毒力。
DOI：
10.1371/journal.ppat.1005604
复制
发表时间：
2016-05
期刊：
影响因子：
6.7
通讯作者：
Horswill AR
中科院分区：
文献类型：
--
作者：
Crosby HA;Schlievert PM;Merriman JA;King JM;Salgado-Pabón W;Horswill AR
Please try later.
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. Staphylococcus causes a wide range of diseases, ranging from skin infections to deadly invasive condition like endocarditis, septicemia, osteomyelitis, and pneumonia. In this work we examine the ArlRS two-component regulatory system, which controls interactions with the host plasma protein fibrinogen. S. aureus normally forms large aggregates called clumps in the presence of fibrinogen, but the arlRS mutant is unable to clump. We demonstrate that ArlRS activates expression of the DNA-binding protein MgrA, and that mgrA is also required for clumping. Transcriptional analysis of an mgrA mutant shows that MgrA regulates expression of eight surface proteins. Expression of these surface proteins affects clumping, possibly by physically interfering with fibrinogen binding. Strains lacking mgrA are less virulent in an endocarditis model, and virulence can be partially restored by deleting genes for three of these surface proteins. An mgrA mutant is also known to have enhanced biofilm formation, and we show that this is partially due to increased production of one of these surface proteins. These results demonstrate that ArlRS and MgrA constitute a regulatory cascade in S. aureus that is crucial for pathogenesis and may be a good candidate to target for drug development.