The GraRS regulatory system controls Staphylococcus aureus susceptibility to antimicrobial host defenses.
BACKGROUND
Modification of teichoic acids with D-alanine by the products of the dlt operon protects Gram-positive bacteria against major antimicrobial host defense molecules such as defensins, cathelicidins, myeloperoxidase or phospholipase. The graRS regulatory genes have recently been implicated in the control of D-alanylation in Staphylococcus aureus.


RESULTS
To determine the impact of the GraRS regulatory system on resistance to antimicrobial host defense mechanisms and virulence of S. aureus, we compared inactivation of S. aureus SA113 wild type and its isogenic graRS deletion mutant by the human cathelicidin LL-37 or human neutrophil granulocytes in vitro, and the ability to cause infection in vivo. We show here that graRS deletion considerably alters bacterial surface charge, increases susceptibility to killing by human neutrophils or the defense peptide LL-37, and attenuates virulence of S. aureus in a mouse infection model.


CONCLUSIONS
Our results indicate that S. aureus can regulate its surface properties in order to overcome innate host defenses.
Cellular and Molecular Microbiology Division, Institute for Medical Microbiology and Hygiene, University of Tübingen, Elfriede-Aulhorn-Str, 6, 72076 Tübingen, Germany. dirk.kraus@med.uni-tuebingen.de
Dirk
D
Kraus
Silvia
S
Herbert
Sascha A
SA
Kristian
Arya
A
Khosravi
Victor
V
Nizet
Friedrich
F
Götz
Andreas
A
Peschel
D000409:Alanine / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology; D054804:Cathelicidins; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005798:Genes, Bacterial; D005809:Genes, Regulator; D006801:Humans; D007113:Immunity, Innate; D007668:Kidney / Q000382:microbiology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D009876:Operon; D010715:Phosphatidylglycerols / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000472:pathogenicity*; D013682:Teichoic Acids / Q000378:metabolism; D014774:Virulence
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D010715:Phosphatidylglycerols; D013682:Teichoic Acids; C002285:lysylphosphatidylglycerol; D045304:Cytochromes c; D008239:Lysine; D000409:Alanine