Nonimmune antibody interactions of Group A Streptococcus M and M-like proteins

Abstract

M and M-like proteins are major virulence factors of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes. These proteins confer resistance against innate and adaptive immune responses by recruiting specific human proteins to the streptococcal surface. Nonimmune recruitment of immunoglobulins G (IgG) and A (IgA) through their fragment crystallizable (Fc) domains by M and M-like proteins was described almost 40 years ago, but its impact on virulence remains unresolved. These interactions have been suggested to be consequential under immune conditions at mucosal surfaces and in secretions but not in plasma, while other evidence suggests importance in evading phagocytic killing in nonimmune blood. Recently, an indirect effect of Fc-binding through ligand-induced stabilization of an M-like protein was shown to increase virulence. Nonimmune recruitment has also been seen to contribute to tissue damage in animal models of autoimmune diseases triggered by S. pyogenes infection. The damage was treatable by targeting Fc-binding. This and other potential therapeutic applications warrant renewed attention to Fc-binding by M and M-like proteins.

The Retropepsin-Type Protease APRc as a Novel Ig-Binding Protein and Moonlighting Immune Evasion Factor ofRickettsia

“…8C ). Since several bacterial nonimmune IgG-binding proteins were also shown to interact with other serum proteins, likely to evade complement-mediated killing more effectively ( 16 , 17 ), these results directed us to test whether APRc can mediate resistance to serum bactericidal activity.…”

“…The significance of the host’s innate surveillance mechanisms for pathogen clearance is demonstrated by the diverse arsenal of virulence determinants and evasive strategies identified in many human-pathogenic bacteria capable of interfering with complement and, thereby, promoting immune evasion ( 7 , 8 ). Bacterial surface proteins capable of nonimmune immunoglobulin (Ig) binding are key players in immune evasion due to protection against complement attack, decreasing opsonization and phagocytosis, or both ( 15 – 17 ). Moreover, a second known function of proteins binding to Ig, without involving the antigen-binding site, is to act as B-cell or immunoglobulin superantigens ( 18 – 20 ).…”

“…There are many Ig-binding proteins, differing significantly in structure, size, binding properties/affinities, and binding sites on the Ig molecules ( 15 , 17 ). The best characterized are from Gram-positive bacteria and include protein A (SpA), Sbi, IsaB, and SSL10 from Staphylococcus aureus ( 15 , 17 , 21 – 23 ), protein M and M-like proteins from group A streptococci ( 16 ), protein G from group C and G streptococci ( 17 , 24 ), and protein L from Finegoldia magna ( 25 ). Although not as well explored, it has been demonstrated that Gram-negative bacteria also express nonimmune Ig-binding proteins.…”

“…They have been found in Histophilus somni ( 26 ); within the pathogenic Yersinia genus, Y. pestis and Y. pseudotuberculosis ( 27 – 29 ); Stenotrophomonas maltophilia ( 30 ); Escherichia coli ( 31 ); different species of Mycoplasma ( 32 – 34 ); and Helicobacter pylori ( 35 ). Importantly, many nonimmune Ig-binding proteins are known to be multifunctional, interacting with other host serum proteins or immune cells, which further contributes to providing resistance against clearance by the host’s innate and adaptive immune systems ( 16 , 17 ).…”

Signaling Peptide SpoV Is Essential for Streptococcus pyogenes Virulence, and Prophylaxis with Anti-SpoV Decreases Disease Severity

“…In addition to human IgG, GAS binds nonspecifically bind IgG from several animal species, including rabbits [31]. The M protein and M-like proteins bind to both IgG and IgA via the Fc region, which inhibits phagocytosis and increases GAS survival in blood [31][32][33]. SfbI binds to the Fc region of IgG, which prevents antibody-dependent cell cytotoxicity (ADCC) by macrophages [34].…”