Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin–mediated neutrophil rolling

Abstract

IntroductionStaphylococcus aureus is a common human pathogen that induces both community-acquired and nosocomial infections. This Grampositive bacterium is well known for its suppurative diseases such as skin-limited abscesses and boils and more seriously endocarditis, sepsis, and toxic shock syndrome. 1,2 Its invasiveness is ascribed to the production of a wide repertoire of cell surface-expressed as well as secreted virulence factors that interfere with host defense. 2,3 Superantigens constitute a large portion of the secreted arsenal of staphylococci and modulate immune responses. They trigger nonspecific activation of T lymphocytes by binding to major histocompatibility complex (MHC) class II molecules on antigenpresenting cells outside the antigen-binding cleft and V ␤ domains of T-cell receptors (TCRs). 4 We have described chemotaxis inhibitory protein of S aureus (CHIPS), an excreted virulence factor of S aureus. 5,6 CHIPS is known to inhibit formylated peptide-and complement factor C5a-induced responses in neutrophils through direct binding to the formyl peptide receptor and C5a receptor (C5aR), respectively. 7 Thereby, CHIPS inhibits the initial activation and migration of neutrophils to the site of infection; thus, it hampers clearance of S aureus by innate immune cells. Recently, the structure of CHIPS consisting of residues 31 to 121 (CHIPS ) was resolved. 8 CHIPS is composed of an ␣-helix packed onto a 4-stranded antiparallel ␤-sheet, a domain also present in the C-terminal domain of superantigens. This protein also revealed to be homologous to the C-terminal domain of staphylococcal superantigen-like 5 (SSL5) and SSL7.SSLs are a family of secreted proteins identified through sequence homology to staphylococcal and streptococcal superantigens. 9 Eleven different SSLs exist that are encoded on staphylococcal pathogenicity island 2 in a conserved order. Staphylococci contain 7 to 11 different SSLs, and their homology varies between 36% and 67%. Allelic variants show 85% to 100% homology. 10,11 Determination of the crystal structures of SSL5 12 and SSL7 13 also revealed their high structural homology to superantigens; the N-terminal oligonucleotide/oligosaccharide-binding fold and the C-terminal ␤-grasp domain characteristic for superantigens are also observed in SSLs. However, residues important for MHC class II and TCR binding of superantigens are not conserved in SSLs, which may explain their inability to display superantigenic activities. 9,10,12 Recently, Langley et al 14 described binding of complement component 5 and immunoglobulin A (IgA) by SSL7, suggesting a role for SSLs in staphylococcal defense against host immune responses. SSL7 was subsequently found to bind the C␣2/C␣3 interface of IgA Fc, which is the adhesion site for the Fc␣RI. 15 So far, no other functions have been linked to the SSLs.Neutrophil recruitment to sites of infection is a multistep process. 16 The initial tethering and rolling of neutrophils on the endothelium of vessel walls during inflammation are mediated by P-selec...

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

“…Interestingly, the functions that have been discovered for SSLs so far have all been linked to immune evasion. SSL5 inhibits neutrophil extravasation (17,18) and phagocyte function (19,20), SSL7 binds IgA and inhibits complement (21), and SSL10 inhibits IgG1-mediated phagocytosis (22,23), blood coagulation (24), and the chemokine receptor CXCR4 (25). In addition to SSL3, also weak TLR2 inhibitory activity was observed for SSL4 (5), but it remains unknown whether that is its dominant function.…”

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

“…However, unlike SE, the SSL proteins do not have superantigen activity, but some have been shown to inhibit key molecules of the host immune system. Both SSL5 (21) and SSL11 (M. C. Chung, B.D.W., H. Baker, R. J. Langley, E. N. Baker, and J.D.F., unpublished data) interact with sialyl-Le x and related oligosaccharides, thereby inhibiting key cellular adhesion processes such as neutrophil transmigration. Notably, SSL7 exhibits multiple activities, including the binding of complement component C5 and serum and mucosal forms of IgA, thereby inhibiting both C5 and fragment crystalline (Fc) receptor for IgA (Fc␣RI)-mediated immunity (22,23).…”

Regulation of Staphylococcal Superantigen-Like Gene, ssl8, Expression in Staphylococcus aureus strain, RN6390

“…1,6,[9][10][11][19][20][21] Their production is controlled by a network of global regulators, which act both positively and negatively depending on the virulence genes and host strains. [2][3][4]9,16,17 We showed here that sarA and rot mutations down-regulated and up-regulated ssl8 expression, respectively, in RN6390, suggesting these two were the positive and negative regulators of ssl8 in this strain (figure 1).…”

“…6,[9][10][11][12] SSL5 interferes with the interaction between PSGL-1 (P-selectin glycoprotein ligand-1) and P-selectin and prevents neutrophil extravasations toward the site of infection.…”