Acute rheumatic fever is a serious autoimmune sequela of pharyngitis caused by certain group A streptococci. One mechanism applied by streptococcal strains capable of causing acute rheumatic fever is formation of an autoantigenic complex with human collagen IV. In some geographic regions with a high incidence of acute rheumatic fever pharyngeal carriage of group C and group G streptococci prevails. Examination of such strains revealed the presence of M-like surface proteins that bind human collagen. Using a peptide array and recombinant proteins with targeted amino acid substitutions, we could demonstrate that formation of collagen complexes during streptococcal infections depends on an octapeptide motif, which is present in collagen binding M and M-like proteins of different ␤-hemolytic streptococcal species. Mice immunized with streptococcal proteins that contain the collagen binding octapeptide motif developed high serum titers of anti-collagen antibodies. In sera of rheumatic fever patients such a collagen autoimmune response was accompanied by specific reactivity against the collagen-binding proteins, linking the observed effect to clinical cases. Taken together, the data demonstrate that the identified octapeptide motif through its action on collagen plays a crucial role in the pathogenesis of rheumatic fever. Eradication of streptococci that express proteins with the collagen binding motif appears advisable for controlling rheumatic fever. Acute rheumatic fever (ARF)3 is one of the most serious diseases caused by streptococci and occurs as an autoimmune sequela of untreated or inadequately treated group A streptococcal pharyngitis (1). ARF and the subsequent rheumatic heart disease (RHD) remain significant causes of cardiovascular disease today (2, 3). The most devastating effects are on children and young adults in their most productive years (2-4). According to a recent estimate more than 15 million people have RHD, more than 0.5 million acquire ARF each year, and about 0.25 million deaths annually are directly attributable to ARF or RHD (2). The fact that penicillin has clearly failed to eradicate ARF and that streptococcal vaccines are still years away from being available underlines the need for novel control strategies (5, 6). Identification of the pathogenic mechanisms underlying ARF is a prerequisite for the development of the necessary diagnostic and preventive approaches.Major virulence factors of streptococci that infect humans are the M and M-like proteins. They exert anti-phagocytic effects (7-10) and facilitate streptococcal survival within polymorph nuclear neutrophils (11). Variability in the N-terminal of M proteins generated more than 100 distinct M serotypes.

This neglected pathogen causes a large portion of these infections.

Some of the variety of Streptococcus pyogenes and Streptococcus dysgalactiae ssp. equisimilis (SDSE) M proteins act as collagen-binding adhesins that facilitate acute infection. Moreover, their potential to trigger collagen autoimmunity has been implicated in the pathogenesis of acute rheumatic fever and attributed to a collagen-binding motif called PARF (peptide associated with rheumatic fever). For the first time we determine the rate of clinical isolates with collagen-binding M proteins that use a PARF motif (A/T/E)XYLXX(L/F)N in a defined geographic region, Vellore in South India. In this region both, incidence of streptococcal infections and prevalence of acute rheumatic fever are high. M proteins with PARF motif conferred collagen-binding activity to 3.9% of 153 S. pyogenes and 10.6% of 255 SDSE clinical isolates from Vellore. The PARF motif occurred in three S. pyogenes and 22 SDSE M protein types. In one of the S. pyogenes and five of the SDSE M proteins that contained the motif, collagen-binding was impaired, due to influences of other parts of the M protein molecule. The accumulated data on the collagen binding activity of certain M protein types allowed a reanalysis of published worldwide emm-typing data with the aim to estimate the rates of isolates that bind collagen via PARF. The results indicate that M proteins, which bind collagen via a PARF motif, are epidemiologically relevant in human infections, not only in Vellore. It is imperative to include the most relevant collagen-binding M types in vaccines. But when designing M protein based vaccines it should be considered that collagen binding motifs within the vaccine antigen remain potential risk factors.

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...

No abstract