Recognition of Staphylococcus aureus by the innate immune system

Abstract

The gram-positive bacterium Staphylococcus aureus is a major pathogen responsible for a variety of diseases ranging from minor skin infections to life-threatening conditions such as sepsis. Cell wall-associated and secreted proteins (e.g., protein A, hemolysins, and phenol-soluble modulin) and cell wall components (e.g., peptidoglycan and alanylated lipoteichoic acid) have been shown to be inflammatory, and these staphylococcal components may contribute to sepsis. On the host side, many host factors have been implicated in the innate detection of staphylococcal components. One class of pattern recognition molecules, Toll-like receptor 2, has been shown to function as the transmembrane component involved in the detection of staphylococcal lipoteichoic acid and phenol-soluble modulin and is involved in the synthesis of inflammatory cytokines by monocytes/macrophages in response to these components. Nod2 (nucleotide-binding oligomerization domain 2) is the intracellular sensor for muramyl dipeptide, the minimal bioactive structure of peptidoglycan, and it may contribute to the innate immune defense against S. aureus. The staphylococcal virulence factor protein A was recently shown to interact directly with tumor necrosis factor receptor 1 in airway epithelium and to reproduce the effects of tumor necrosis factor alpha. Finally, peptidoglycan recognition protein L is an amidase that inactivates the proinflammatory activities of peptidoglycan. However, peptidoglycan recognition protein L probably plays a minor role in the innate immune response to S. aureus. Thus, several innate immunity receptors may be implicated in host defense against S. aureus.

FIG. 1.

Structures of teichoic acid (A) and lipoteichoic acid (B) of S. aureus (data from references and 163). NAG, N-acetylglucosamine.

FIG. 2.

Structure of peptidoglycan of S. aureus and several other bacteria. The peptidoglycan of gram-negative bacteria and gram-positive bacilli is indicated on the right. Digestion by different enzymes (glucosaminidase, muramidase, amidase, and endopeptidase) is shown by dotted arrows. MDP structure is indicated in the dotted square. NAG, N-acetylglucosamine; NAM, N-acetylmuramic acid; m-DAP, m-diaminopimelic acid.

FIG. 3.

Action of staphylococcal components to promote immune responses from immune cells (data from reference 63). FPR, formylated peptide receptor.

FIG. 4.

Domain structure of TLR2 (A) and Nod2 (B). Numbers correspond to amino acid residues. A. TLR2 structure (data from references and 118). ECD, extracellular domain; TMD, transmembrane domain; ICD, intracellular domain; TIR, Toll/IL-1 receptor domain. The regions homologous to LRRs are indicated by square boxes, and LRR-like motifs are indicated by boxes with an asterisk. B. Nod2 structure (data from reference 141). CARD, caspase-activating and recruitment domain; NBS, nucleotide binding site and LRR domain.

FIG. 5.

Different signaling pathways of TLR2, Nod, and TNFR1 in response to ligand, resulting in activation of NF-κB, the nuclear transcriptional factor responsible for regulation of the immune response genes (data from references , , and 194). RIP1, receptor-interacting protein 1; FADD, Fas-associated death domain protein; TRAF2, TNF receptor-associated factor 2; PI3K, phosphatidylinositol 3-kinase composed of two subunits (p85 and p110).