A novel bacterial resistance mechanism against human group IIA-secreted phospholipase A2: role of Streptococcus pyogenes sortase A

J Immunol. 2011 Dec 15;187(12):6437-46. doi: 10.4049/jimmunol.1100499. Epub 2011 Nov 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacyltransferases / physiology*
  • Animals
  • Bacterial Proteins / physiology*
  • Cysteine Endopeptidases / physiology*
  • Disease Models, Animal
  • Drug Resistance, Bacterial / genetics
  • Drug Resistance, Bacterial / immunology*
  • Female
  • Group II Phospholipases A2 / antagonists & inhibitors
  • Group II Phospholipases A2 / deficiency
  • Group II Phospholipases A2 / genetics
  • Group II Phospholipases A2 / metabolism*
  • Group II Phospholipases A2 / physiology
  • Humans
  • Immune Evasion / genetics
  • Immunity, Innate / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Streptococcal Infections / genetics
  • Streptococcal Infections / immunology*
  • Streptococcal Infections / microbiology*
  • Streptococcus pyogenes / enzymology*

Substances

  • Bacterial Proteins
  • Aminoacyltransferases
  • sortase A
  • Group II Phospholipases A2
  • PLA2G2A protein, human
  • Pla2g2a protein, mouse
  • Cysteine Endopeptidases