{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:27:47Z","timestamp":1792045667225,"version":"4.4.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T00:00:00Z","timestamp":1629072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["20ZR1410000"],"award-info":[{"award-number":["20ZR1410000"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072249"],"award-info":[{"award-number":["82072249"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81991532"],"award-info":[{"award-number":["81991532"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671982"],"award-info":[{"award-number":["81671982"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970855"],"award-info":[{"award-number":["81970855"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Methicillin-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA) is a common cause of both community- and hospital-associated infections. The antibiotic resistance and virulence characteristics of MRSA are largely regulated by two-component signal transduction systems (TCS) including the <jats:italic>graRS<\/jats:italic> TCS. To make a relatively comprehensive insight into <jats:italic>graRS<\/jats:italic> TCS in MRSA, the bioinformatics analysis of dataset GSE26016 (a <jats:italic>S. aureus<\/jats:italic> HG001 WT strain vs. the \u0394<jats:italic>graRS<\/jats:italic> mutant) from Gene Expression Omnibus (GEO) database was performed, and a total of 563 differentially expressed genes (DEGs) were identified. GO analysis revealed that the DEGs were mainly enriched in the \u201c<jats:italic>de novo<\/jats:italic>\u201d IMP biosynthetic process, lysine biosynthetic process <jats:italic>via<\/jats:italic> diaminopimelate, and pathogenesis; and they were mainly enriched in purine metabolism, lysine biosynthesis, and monobactam biosynthesis in KEGG analysis. WGCNA suggested that the turquoise module was related to the blue module, and the genes in these two modules were associated with <jats:italic>S. aureus<\/jats:italic> virulence and infection. To investigate the role of <jats:italic>graRS<\/jats:italic> in bacterial virulence, a <jats:italic>graRS<\/jats:italic> knockout mutant (\u0394<jats:italic>graRS<\/jats:italic>) was constructed using MRSA USA500 2,395 strain as a parent strain. Compared to the wild-type strain, the USA500\u0394<jats:italic>graRS<\/jats:italic> showed reduced staphyloxanthin production, retarded coagulation, weaker hemolysis on blood agar plates, and a decreased biofilm formation. These altered phenotypes were restored by the complementation of a plasmid-expressed <jats:italic>graRS<\/jats:italic>. Meanwhile, an expression of the virulence-associated genes (<jats:italic>coa<\/jats:italic>, <jats:italic>hla<\/jats:italic>, <jats:italic>hlb<\/jats:italic>, <jats:italic>agrA<\/jats:italic>, and <jats:italic>mgrA<\/jats:italic>) was downregulated in the \u0394<jats:italic>graRS<\/jats:italic> mutant. Consistently, the A549 epithelial cells invasion of the \u0394<jats:italic>graRS<\/jats:italic> mutant was 4-fold lower than that of the USA500 wild-type strain. Moreover, on the <jats:italic>Galleria mellonella<\/jats:italic> infection model, the survival rate at day 5 post infection in the USA500\u0394<jats:italic>graRS<\/jats:italic> group (55%) was obviously higher than that in the USA500 group (20%), indicating <jats:italic>graRS<\/jats:italic> knockout leads to a decreased virulence <jats:italic>in vivo<\/jats:italic>. In addition, the deletion of the <jats:italic>graRS<\/jats:italic> in the MRSA USA500 strain resulted in its increased susceptibilities to ampicillin, oxacillin, vancomycin, and gentamicin. Our work suggests that the <jats:italic>graRS<\/jats:italic> TCS plays an important role in regulating <jats:italic>S. aureus<\/jats:italic> virulence <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> and modulate bacterial resistance to various antibiotics.<\/jats:p>","DOI":"10.3389\/fmicb.2021.727104","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T13:51:01Z","timestamp":1629121861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["The Role of graRS in Regulating Virulence and Antimicrobial Resistance in Methicillin-Resistant Staphylococcus aureus"],"prefix":"10.3389","volume":"12","author":[{"given":"Le","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfei","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunquan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1080\/22221751.2019.1595984","article-title":"The role of ArlRS in regulating oxacillin susceptibility in methicillin-resistant Staphylococcus aureus indicates it is a potential target for antimicrobial resistance breakers","volume":"8","author":"Bai","year":"2019","journal-title":"Emerg. 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