A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains

Srikanth Mairpady Shambat, Nikolai Siemens, Ian R. Monk, Disha B. Mohan, Santhosh Mukundan, Karthickeyan Chella Krishnan, Sushma Prabhakara, Johanna Snäll, Angela Kearns, Francois Vandenesch, Mattias Svensson, Malak Kotb, Balasubramanian Gopal, Gayathri Arakere, Anna Norrby-Teglund

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number31360
JournalScientific reports
Volume6
DOIs
StatePublished - Aug 11 2016

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Methicillin-Resistant Staphylococcus aureus
Point Mutation
Amino Acid Substitution
Skin
Phenotype
Virulence
Tyrosine
Infection
Inflammasomes
Soft Tissue Infections
Tropism
Bacterial Proteins
Autophagy
Cysteine
Staphylococcus aureus
Membrane Proteins
Up-Regulation
Clone Cells
homocysteine-thiolactone-nicotinamide
Pathology

ASJC Scopus subject areas

  • General

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A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains. / Mairpady Shambat, Srikanth; Siemens, Nikolai; Monk, Ian R.; Mohan, Disha B.; Mukundan, Santhosh; Krishnan, Karthickeyan Chella; Prabhakara, Sushma; Snäll, Johanna; Kearns, Angela; Vandenesch, Francois; Svensson, Mattias; Kotb, Malak; Gopal, Balasubramanian; Arakere, Gayathri; Norrby-Teglund, Anna.

In: Scientific reports, Vol. 6, 31360, 11.08.2016.

Research output: Contribution to journalArticle

Mairpady Shambat, S, Siemens, N, Monk, IR, Mohan, DB, Mukundan, S, Krishnan, KC, Prabhakara, S, Snäll, J, Kearns, A, Vandenesch, F, Svensson, M, Kotb, M, Gopal, B, Arakere, G & Norrby-Teglund, A 2016, 'A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains', Scientific reports, vol. 6, 31360. https://doi.org/10.1038/srep31360
Mairpady Shambat, Srikanth ; Siemens, Nikolai ; Monk, Ian R. ; Mohan, Disha B. ; Mukundan, Santhosh ; Krishnan, Karthickeyan Chella ; Prabhakara, Sushma ; Snäll, Johanna ; Kearns, Angela ; Vandenesch, Francois ; Svensson, Mattias ; Kotb, Malak ; Gopal, Balasubramanian ; Arakere, Gayathri ; Norrby-Teglund, Anna. / A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains. In: Scientific reports. 2016 ; Vol. 6.
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