Group G Streptococcal IgG Binding Molecules FOG and Protein G Have Different Impacts on Opsonization by C1q

Abstract

Recent epidemiological data on diseases caused by ␤-hemolytic streptococci belonging to Lancefield group C and G (GCS,GGSStreptococci of the Lancefield group G and C (GGS 2 and GCS) have long been considered as animal pathogens, being a minor threat to human carriers. Carriage of GCS and GGS in the throat and on the skin is often asymptomatic. However, reports from different parts of the world are accumulating demonstrating that they are emerging as important human pathogens (1-4). Individual processes contributing to the immune defense against GGS are still elusive, and the knowledge about how GGS undermine and obstruct the actions of the immune system is fragmentary. Before the development of a specific immune response, the innate immune system constitutes a first line of defense against intruding bacteria. Part of the innate immune defense is the complement system that has two major functions. One is to kill bacteria by forming lytic complexes on the bacterial membrane, referred to as membrane attack complex. The other one is to facilitate the actions of the cellular immune response. The complement cascade produces anaphylatoxins to attract phagocytes; other complement reactions opsonize the bacteria, promoting extracellular bactericidal actions and phagocytosis (5-8).Bacteria have evolved diverse protective mechanisms to prevent the actions of the complement system. The membrane attack complex is thought to be inefficient in killing Grampositive bacteria due to their resistant cell wall (9). C5a-peptidase of Streptococcus pyogenes, which has a homologue in GGS, cleaves and thereby inactivates a potent anaphylatoxin (10, 11). M proteins of S. pyogenes prevent opsonization by C4b by recruiting plasma proteins like fibrinogen or C4b-binding protein. A recent study suggests that fibrinogen bound to M protein interferes with the deposition of C4b2a, the C3 convertase of the classical pathway, on the bacterial surface (12). A recently defined fibrinogen-binding M-like protein of GGS referred to as FOG was shown to exert anti-phagocytic activity on neutrophils by forming fibrinogen aggregates (13). The complement cascade can be initiated by three different pathways; that is, the classical, the lectin, or the alternative pathway. A triggering step of the classical pathway is the binding of factor C1q to aggregated or antigen-bound IgG. Factor C1q together with the serine proteases C1r and C1s forms the C1 complex. The interaction with IgG induces conformational changes in C1q that lead to the activation of the serine proteases of the C1 complex. This sets off the classical pathway by cleaving C2 and C4, thus leading to the formation of opsonins and anaphylatoxins (5). Moreover, C1q itself acts as an opsonin, eliciting antibacterial actions of phagocytes (7,8,14).GCS and GGS accumulate IgG on their surface by non-immune binding. A major protein that is responsible for the high capacity accumulation of IgG on GGS is protein G (15). Here we demonstrate for the first time that FOG also contributes in * This work was sup...

A Common Theme in Interaction of Bacterial Immunoglobulin-binding Proteins with Immunoglobulins Illustrated in the Equine System

“…Thus the approach and binding of such a large molecule as C1q would be compromised, resulting in more complete inhibition of the complement pathway. Support for this notion comes from related studies with protein G. Although one study found soluble streptococcal protein G unable to block both C1q binding to IgG and complementmediated lysis of IgG-sensitized red blood cells (42), another demonstrated that, when IgG is bound by bacterial cell-surface protein G, interaction with C1q is completely blocked (44). The authors of the second study proposed that the presence of protein G in a defined orientation and spacing on the streptococcal cell surface facilitates inhibition of the interaction of C1q with protein G-bound IgG.…”

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

“…GGS wild-type strain G45 was isolated at the Royal Brisbane Hospital in Brisbane, Australia. Two isogenic mutant strains G45D PG and G45D FOG (Nitsche-Schmitz et al, 2007), lacking protein G or protein FOG, respectively, were also used. Bacteria were grown overnight in ToddHewitt broth (Difco/BD) supplemented with 0.2 % yeast extract (Oxoid) (THY) at 37 uC, in the presence of 5 % CO 2 .…”

“…Two main proteins found on the surface of GGS, protein G and FOG, have been the primary focus of studies regarding bacterial interactions with the human host (Johansson et al, 2004;Nitsche-Schmitz et al, 2007;Egesten et al, 2011). Protein G is the main IgG-binding protein of GGS and exhibits high affinity for IgG from different species (Björck & Kronvall, 1984).…”

Binding of Albumin Promotes Bacterial Survival at the Epithelial Surface

“…Streptococci were routinely grown in Todd Hewitt broth (Difco) containing yeast extract (2 g/liter; Oxoid Ltd.) in 5% CO 2 at 37°C. The isogenic mutants G45⌬FOG and G45⌬G, lacking protein FOG and protein G, respectively, were grown in the presence of erythromycin (1 g/ml) to maintain the knocked out phenotype (32).…”