title: A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections. One of the highly successful and rapidly disseminating clones is MRSA ST22 commonly associated with skin tropism. Here we show that a naturally occurring single amino acid substitution (tyrosine to cysteine) at position 223 of AgrC determines starkly different ST22 S. aureus virulence phenotypes, e.g. cytotoxic or colonizing, as evident in both in vitro and in vivo skin infections. Y223C amino acid substitution destabilizes AgrC-AgrA interaction leading to a colonizing phenotype characterized by upregulation of bacterial surface proteins. The colonizing phenotype strains cause less severe skin tissue damage, show decreased susceptibility towards the antimicrobial LL-37 and induce autophagy. In contrast, cytotoxic strains with tyrosine at position 223 of AgrC cause infections characterized by inflammasome activation and severe skin tissue pathology. Taken together, the study demonstrates how a single amino acid substitution in the histidine kinase receptor AgrC of ST22 strains determines virulence properties and infection outcome.
authors: Karolinska Institutet, Center for Infectious Medicine, Karolinska University Hospital Huddinge, 141 86, Sweden.
authors: Srikanth
authors: S
authors: Mairpady Shambat
authors: Karolinska Institutet, Center for Infectious Medicine, Karolinska University Hospital Huddinge, 141 86, Sweden.
authors: Nikolai
authors: N
authors: Siemens
authors: Department of Microbiology and Immunology, University of Melbourne, Victoria, 3010, Australia.
authors: Ian R
authors: IR
authors: Monk
authors: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
authors: Disha B
authors: DB
authors: Mohan
authors: Department of Basic Sciences, School of Medicine and Health Sciences, University of North, Dakota, ND, 58202-9037, USA.
authors: Santhosh
authors: S
authors: Mukundan
authors: Department of Basic Sciences, School of Medicine and Health Sciences, University of North, Dakota, ND, 58202-9037, USA.
authors: Karthickeyan Chella
authors: KC
authors: Krishnan
authors: Society for Innovation and Development, Indian Institute of Science, Bangalore, 560012, India.
authors: Sushma
authors: S
authors: Prabhakara
authors: Karolinska Institutet, Center for Infectious Medicine, Karolinska University Hospital Huddinge, 141 86, Sweden.
authors: Johanna
authors: J
authors: Snäll
authors: National Infection Service, Public Health England (PHE), Colindale, London, NW95EQ, UK.
authors: Angela
authors: A
authors: Kearns
authors: CIRI, International Center for Infectiology Research, Inserm, U1111, CNRS UMR5308, Université Lyon 1, École Normale, Supérieure de Lyon, French.|French National Reference Center for Staphylococci, Hospices Civils de Lyon, 69677, Bron Cedex, France.
authors: Francois
authors: F
authors: Vandenesch
authors: Karolinska Institutet, Center for Infectious Medicine, Karolinska University Hospital Huddinge, 141 86, Sweden.
authors: Mattias
authors: M
authors: Svensson
authors: Department of Basic Sciences, School of Medicine and Health Sciences, University of North, Dakota, ND, 58202-9037, USA.
authors: Malak
authors: M
authors: Kotb
authors: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India.
authors: Balasubramanian
authors: B
authors: Gopal
authors: Society for Innovation and Development, Indian Institute of Science, Bangalore, 560012, India.
authors: Gayathri
authors: G
authors: Arakere
authors: Karolinska Institutet, Center for Infectious Medicine, Karolinska University Hospital Huddinge, 141 86, Sweden.
authors: Anna
authors: A
authors: Norrby-Teglund
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D051379:Mice; D010641:Phenotype; D017354:Point Mutation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D013207:Staphylococcal Skin Infections / Q000382:microbiology*; D014443:Tyrosine / Q000235:genetics; D056189:Viral Tropism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D014443:Tyrosine; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus; D003545:Cysteine; D054804:Cathelicidins