title: A novel bacterial resistance mechanism against human group IIA-secreted phospholipase A2: role of Streptococcus pyogenes sortase A.
abstract: Human group IIA-secreted phospholipase A(2) (sPLA(2)-IIA) is a bactericidal molecule important for the innate immune defense against Gram-positive bacteria. In this study, we analyzed its role in the host defense against Streptococcus pyogenes, a major human pathogen, and demonstrated that this bacterium has evolved a previously unidentified mechanism to resist killing by sPLA(2)-IIA. Analysis of a set of clinical isolates demonstrated that an ~500-fold higher concentration of sPLA(2)-IIA was required to kill S. pyogenes compared with strains of the group B Streptococcus, which previously were shown to be sensitive to sPLA(2)-IIA, indicating that S. pyogenes exhibits a high degree of resistance to sPLA(2)-IIA. We found that an S. pyogenes mutant lacking sortase A, a transpeptidase responsible for anchoring LPXTG proteins to the cell wall in Gram-positive bacteria, was significantly more sensitive (~30-fold) to sPLA(2)-IIA compared with the parental strain, indicating that one or more LPXTG surface proteins protect S. pyogenes against sPLA(2)-IIA. Importantly, using transgenic mice expressing human sPLA(2)-IIA, we showed that the sortase A-mediated sPLA(2)-IIA resistance mechanism in S. pyogenes also occurs in vivo. Moreover, in this mouse model, we also showed that human sPLA(2)-IIA is important for the defense against lethal S. pyogenes infection. Thus, we demonstrated a novel mechanism by which a pathogenic bacterium can evade the bactericidal action of sPLA(2)-IIA and we showed that sPLA(2)-IIA contributes to the host defense against S. pyogenes infection.
authors.affiliation: Division of Medical Microbiology, Department of Laboratory Medicine, Lund University, 22362 Lund, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Movert
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
authors.forename: Thomas
authors.initials: T
authors.lastname: Areschoug
mesh_terms: D019881:Aminoacyltransferases / Q000502:physiology*; D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics / Q000276:immunology*; D005260:Female; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C120542:sortase A; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; C516288:Pla2g2a protein, mouse; D003546:Cysteine Endopeptidases