Identification of a Streptococcal Octapeptide Motif Involved in Acute Rheumatic Fever

Abstract

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.

Host–Pathogen Interactions in Streptococcal Immune Sequelae

“…Elevated titers of autoantibodies in the sera of ARF/RHD patients Dinkla et al, 2007;Dinkla et al, 2003;Guilherme et al, 2006) and deposition of immunoglobulin and complement in the affected hearts indicate that humoral immunity is crucially involved in ARF pathogenesis. Moreover, the early processes in rheumatic carditis involve cellular immune responses.…”

“…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.…”

“…Alternatively, M proteins trigger autoimmune response by a mechanism that requires binding of collagen (Barroso et al, 2009;Dinkla et al, 2007;Dinkla et al, 2003). The rheumatogenic M protein of type 3 (Stollerman, 1969) that caused ARF and ARF-like symptoms in vaccinees (Massell et al, 1969), binds collagens to the streptococcal surface and causes their aggregation (Dinkla et al, 2003).…”

Soft tissue infection caused by Streptococcus dysgalactiae subsp. equisimilis possessing group Aantigen: a and review of the literature

“…Sporadically, infections caused by SDSE are followed by acute glomerulonephritis [65][66][67]. There is also a growing number of evidence for the connection between SDSE and rheumatic fever [46,68].…”

Surface proteins of group G Streptococcus in different phases of growth: patterns of production and implications for the host–bacteria relationship

“…Group G streptococci (GGS) are important human pathogens, causing a range of infections such as pharyngitis, pyoderma and sepsis, as well as post-infection sequelae (Bramhachari et al, 2010;Brandt & Spellerberg, 2009;Dinkla et al, 2007;Takahashi et al, 2011). Among their virulence factors are M-like proteins and protein G (PG).…”