Interaction between Complement Regulators andStreptococcus pyogenes: Binding of C4b-Binding Protein and Factor H/Factor H-Like Protein 1 to M18 Strains Involves Two Different Cell Surface Molecules

Abstract

Streptococcus pyogenes, or group A Streptococcus, is one of the most frequent causes of pharyngitis and skin infections in humans. Many virulence mechanisms have been suggested to be involved in the infectious process. Among them is the binding to the bacterial cell surface of the complement regulatory proteins factor H, factor H-like protein 1 (FHL-1), and C4b-binding protein. Previous studies indicate that binding of these three regulators to the streptococcal cell involves the M protein encoded by the emm gene. M-type 18 strains are prevalent among clinical isolates and have been shown to interact with all three complement regulators simultaneously. Using isogenic strains lacking expression of the Emm18 or the Enn18 proteins, we demonstrate in this study that, in contradistinction to previously described S. pyogenes strains, M18 strains bind the complement regulators factor H, FHL-1, and C4b-binding protein through two distinct cell surface proteins. Factor H and FHL-1 bind to the Emm18 protein, while C4BP binds to the Enn18 protein. We propose that expression of two distinct surface structures that bind complement regulatory proteins represents a unique adaptation of M18 strains that enhances their resistance to opsonization by human plasma and increases survival of this particular S. pyogenes strain in the human host. These new findings illustrate that S. pyogenes has evolved diverse mechanisms for recruitment of complement regulatory proteins to the bacterial surface to evade immune clearance in the human host.

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

“…In addition to inhibition of the alternative pathway, several bacteria (e.g., Moraxella catarrhalis, S. pyogenes, E. coli K1, and H. influenzae) bind C4BP and are shielded against the classical and lectin pathways (49 -51). Interestingly, many species, C. albicans, Borrelia recurrentis, and S. pyogenes, among others, have been shown to bind both FH and C4BP (26,(52)(53)(54)(55). We have recently demonstrated that non-typeable H. influenzae binds C4BP (30).…”

Mechanisms of Resistance ofPorphyromonas gingivalisto Killing by Serum Complement

“…Complement resistance brought about by binding of soluble host-derived complement control proteins factor H and C4 binding protein onto cell surfaces has been confirmed for several strains, including N. gonorrhoeae (28,29) and Streptococcus pyogenes (27). Escherichia coli can acquire resistance by binding of host-derived glycophosphoinositol-anchored protectin (CD59), which inhibits C5b-9 neoantigen expression.…”

Fhb, a Novel Factor H-Binding Surface Protein, Contributes to the Antiphagocytic Ability and Virulence of Streptococcus suis

“…One important component of host immunity to bacterial pathogens is the complement system. A number of cell surface proteins in pathogenic bacteria were identified as antiphagocytic factors to inhibit complement activity, e.g., PspC protein in Streptococcus pneumoniae (17), M-related proteins and Scl1 protein in group A Streptococcus (11,42), and complement regulator-acquiring surface proteins (CRASPs) of Borrelia burgdorferi (26). However, the mechanisms used by S. suis to evade innate immune defenses remain unclear, except for capsular polysaccharide (CPS) and SLY, which were found to have antiphagocytic activity (12,34,48).…”