@article{58cd8a90a2344aa7aa712b1f08374644,
title = "MRSA lineage USA300 isolated from bloodstream infections exhibit altered virulence regulation",
abstract = "The epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 lineage has recently become a leading cause of hospital-associated bloodstream infections (BSIs). Here, we leveraged this recent introduction into hospitals and the limited genetic variation across USA300 isolates to identify mutations that contribute to its success in a new environment. We found that USA300 BSI isolates exhibit altered virulence regulation. Using comparative genomics to delineate the genes involved in this phenotype, we discovered repeated and independent mutations in the transcriptional regulator sarZ. Mutations in sarZ resulted in increased virulence of USA300 BSI isolates in a murine model of BSI. The sarZ mutations derepressed the expression and production of the surface protein ClfB, which was critical for the pathogenesis of USA300 BSI isolates. Altogether, these findings highlight ongoing evolution of a major MRSA lineage and suggest USA300 strains can optimize their fitness through altered regulation of virulence.",
keywords = "GWAS, MRSA, SarZ, USA300, bloodstream infections, gene regulation, pathogenesis, virulence",
author = "Sophie Dyzenhaus and Sullivan, {Mitchell J.} and Bremy Alburquerque and Daiane Boff and {van de Guchte}, Adriana and Marilyn Chung and Yi Fulmer and Richard Copin and Ilmain, {Juliana K.} and Anna O'Keefe and Altman, {Deena R.} and Stubbe, {Fran{\c c}ois Xavier} and Magdalena Podkowik and Dupper, {Amy C.} and Bo Shopsin and {van Bakel}, Harm and Torres, {Victor J.}",
note = "Funding Information: We thank members of the Torres, Shopsin, and van Bakel laboratories for insightful discussions and comments on this manuscript. We thank the NYU Langone Genome Technology Center (GTC) for expert support and BEI Resources for providing the transposon mutant NR-47110. pIMAY ∗ was a gift from Dr. Angelika Grundling (Addgene plasmid # 121441; http://n2t.net/addgene:121441 ; RRID:Addgene_121441) and the anti-ClfB serum was a gift from Dr. Joan Geoghegan. Graphical abstract was created with BioRender.com . This work was supported in part by the National Institute of Allergy and Infectious Diseases award numbers R01s AI099394 , AI105129 to V.J.T., AI137336 , AI140754 to B.S. and V.J.T., and AI119145 to H.v.B. The GTC is partially supported by the Isaac Perlmutter Cancer Center Support grant P30CA016087 from the National Cancer Institute . The work reported in this paper was also supported by the Office of Research Infrastructure of the National Institutes of Health (NIH) under award numbers S10OD018522 and S10OD026880 . V.J.T. is a Burroughs Wellcome Fund Investigator in the pathogenesis of infectious diseases. Funding Information: We thank members of the Torres, Shopsin, and van Bakel laboratories for insightful discussions and comments on this manuscript. We thank the NYU Langone Genome Technology Center (GTC) for expert support and BEI Resources for providing the transposon mutant NR-47110. pIMAY∗ was a gift from Dr. Angelika Grundling (Addgene plasmid # 121441; http://n2t.net/addgene:121441; RRID:Addgene_121441) and the anti-ClfB serum was a gift from Dr. Joan Geoghegan. Graphical abstract was created with BioRender.com. This work was supported in part by the National Institute of Allergy and Infectious Diseases award numbers R01s AI099394, AI105129 to V.J.T. AI137336, AI140754 to B.S. and V.J.T. and AI119145 to H.v.B. The GTC is partially supported by the Isaac Perlmutter Cancer Center Support grant P30CA016087 from the National Cancer Institute. The work reported in this paper was also supported by the Office of Research Infrastructure of the National Institutes of Health (NIH) under award numbers S10OD018522 and S10OD026880. V.J.T. is a Burroughs Wellcome Fund Investigator in the pathogenesis of infectious diseases. S.D. M.J.S. B.S. H.v.B. and V.J.T. designed the study. S.D. performed all the experiments and M.J.S. performed the computational analyses with help from R.C. and F.-X.S. A.V.d.G. and M.C. prepared clinical isolates and performed DNA extractions for whole-genome sequencing at Mount Sinai. Y.F. collected SSTI clinical isolates and along with M.P. performed DNA extractions for whole-genome sequencing at NYU. B.A. generated and helped analyze RNA-seq data. D.R.A. and A.C.D. provided isolate metadata. J.K.I. and A.O'K. helped generate the anti-SarZ serum. D.B. helped perform the murine skin infection experiments. S.D. M.J.S. B.S. H.v.B. and V.J.T. wrote the manuscript, and all authors commented on the manuscript. V.J.T. is an inventor on patents and patent applications filed by New York University, which are currently under commercial license to Janssen Biotech Inc. Janssen Biotech Inc. provides research funding and other payments associated with a licensing agreement. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2023",
month = feb,
day = "8",
doi = "10.1016/j.chom.2022.12.003",
language = "English",
volume = "31",
pages = "228--242.e8",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "2",
}