Staphylococcus aureus Complement-Independent Phagocytosis of Recognition Protein That Induces Human SAP Is a Novel Peptidoglycan

The human pathogen Staphylococcus aureus is responsible for many community-acquired and hospital-associated infections and is associated with high mortality. Concern over the emergence of multidrug-resistant strains has renewed interest in the elucidation of host mechanisms that defend against S. aureus infection. We recently demonstrated that human serum mannose-binding lectin binds to S. aureus wall teichoic acid (WTA), a cell wall glycopolymer—a discovery that prompted further screening to identify additional serum proteins that recognize S. aureus cell wall components. In this report, we incubated human serum with 10 different S. aureus mutants and determined that serum amyloid P component (SAP) bound specifically to a WTA-deficient S. aureus DtagO mutant, but not to tagO-complemented, WTA-expressing cells. Biochemical characterization revealed that SAP recognizes bacterial peptidoglycan as a ligand and that WTA inhibits this interaction. Although SAP binding to peptidoglycan was not observed to induce complement activation, SAP-bound DtagO cells were phagocytosed by human polymorphonuclear leuko-cytes in an FcgR-dependent manner. These results indicate that SAP functions as a host defense factor, similar to other pepti-doglycan recognition proteins and nucleotide-binding oligomerization domain–like receptors. I nnate immunity constitutes the first line of host defense and recognizes evolutionarily conserved molecular patterns of pathogenic microbes using pattern recognition receptors (PRRs) (1). Based on their localization, PRRs are classified as either cell-associated receptors, including the Toll-like receptors (2) and scavenger receptors (3), or fluid-phase molecules (4). Fluid-phase molecules, such as collectins, ficolins, and pentraxins, constitute the humoral arm of the innate immune system and are generally believed to represent the functional ancestors of Abs (5). The pentraxin family can be divided into two subclasses, the short-chain pentraxins, which include C-reactive protein (CRP) and serum amyloid P component (SAP), and the long-chain pentraxins, which contain an additional N-terminal domain. PTX3, a long-chain pentraxin, is produced by macrophages and myeloid den-dritic cells in response to proinflammatory stimuli (6–8). Whereas human CRP and mouse SAP are major acute-phase proteins (9), human SAP is a constitutive protein in blood (10). SAP, named for its universal presence in amyloid deposits, is the precursor of amyloid P component in tissue, where it may promote the development of pathogenic amyloid deposits and prevent their degradation. Both SAP and CRP have been reported to recognize numerous pathogenic bacteria and fungi and activate the classical complement pathway via C1q (8, 11). SAP is a conserved, circulating protein that exhibits calcium-dependent binding to various ligand molecules on the surface …