Region Specific and Worldwide Distribution of Collagen-Binding M Proteins with PARF Motifs among Human Pathogenic Streptococcal Isolates

Abstract

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.

Host–Pathogen Interactions in Streptococcal Immune Sequelae

“…This suggests principal mechanistic differences as compared to the interaction between collagen and PARF, Thus, it remains unexamined whether M1 and other PARF-negative collagen-binding M proteins are able to trigger a collagen autoimmune response. If they do, the epidemiological relevance of collagen-binding M proteins and collagen autoimmunity in the pathogenesis of ARF and RHD may be even higher than indicated by the previous estimates (Reißmann et al, 2012).…”

“…It depends on an (A/T/E)XYLXX(L/F)N octapeptide motif that is located in the N-terminal type-specific part of the M protein (Fig. 1) (Barroso et al, 2009;Dinkla et al, 2007;Reißmann et al, 2012) and contributes to acute infections by facilitating streptococcal colonization of the ECM (Dinkla et al, 2003;Nitsche et al, 2006). When injected into mice, M3 protein and other collagen-binding M proteins that carry the (A/T/E)XYLXX(L/F)N motif trigger production of anti-collagen IV antibodies.…”

“…Based on a world-spanning meta-analysis of emm-typing studies ) type 3 is of particular relevance, amounting to 7% of the S. pyogenes isolates (Reißmann et al, 2012). Only M proteins with the PARF motif are shown to endow streptococci with a high binding capacity for a variety of collagens, including collagen IV.…”

“…Regionally and temporarily, rates of isolates with collagen binding M proteins with PARF motif that trigger collagen autoimmunity exceed 10% in different regions of the globe both, for SDSE or S. pyogenes (Reißmann et al, 2012). More than 10% of clinical SDSE isolates collected in Southern India bore such collagen-binding M proteins.…”

Bacterial adhesion to animal tissues: protein determinants for recognition of extracellular matrix components

“…Streptococcocal M proteins mediate high-affinity interaction with collagen IV via an N-terminal PARF (peptide associated with rheumatic fever) motif (Reissmann et al, 2012). The N-terminal region of CbsA (collagen-binding S-layer protein A) binds to collagens I and IV (Antikainen et al, 2002).…”