Crucial Role of the CB3-Region of Collagen IV in PARF-Induced Acute Rheumatic Fever

Abstract

Acute rheumatic fever (ARF) and rheumatic heart disease are serious autoimmune sequelae to infections with Streptococcus pyogenes. Streptococcal M-proteins have been implicated in ARF pathogenesis. Their interaction with collagen type IV (CIV) is a triggering step that induces generation of collagen-specific auto-antibodies. Electron microscopy of the protein complex between M-protein type 3 (M3-protein) and CIV identified two prominent binding sites of which one is situated in the CB3-region of CIV. In a radioactive binding assay, M3-protein expressing S. pyogenes and S. gordonii bound the CB3-fragment. Detailed analysis of the interactions by surface plasmon resonance measurements and site directed mutagenesis revealed high affinity interactions with dissociation constants in the nanomolar range that depend on the recently described collagen binding motif of streptococcal M-proteins. Because of its role in the induction of disease-related collagen autoimmunity the motif is referred to as “peptide associated with rheumatic fever” (PARF). Both, sera of mice immunized with M3-protein as well as sera from patients with ARF contained anti-CB3 auto-antibodies, indicating their contribution to ARF pathogenesis. The identification of the CB3-region as a binding partner for PARF directs the further approaches to understand the unusual autoimmune pathogenesis of PARF-dependent ARF and forms a molecular basis for a diagnostic test that detects rheumatogenic streptococci.

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Identification of active variants of PARF in human pathogenic group C and group G streptococci leads to an amended description of its consensus motif

“…M proteins of certain emm types facilitate host adhesion by binding collagens (Dinkla et al, 2003;Nitsche et al, 2006), which are abundant structural proteins in the mammalian extracellular matrix (Bosman and Stamenkovic, 2003;Gelse et al, 2003). A sequence of 8 amino acids AXYLZZLN was found to be the collagen-binding motif of the M3 protein of S. pyogenes and the M protein FOG of S. equisimilis, and recent work shows that this motif enables these M proteins to bind the CB3-region of collagen IV (CIV) (Dinkla et al, 2009). This region is part of a triplehelical domain and bears a binding site for a1-and a2-integrins.…”

M-Protein Analysis of Streptococcus pyogenes Isolates Associated with Acute Rheumatic Fever in New Zealand

“…However, more recent epidemiological studies in areas where ARF is common today have found that ARF is not restricted to these rheumatogenic strains (4), raising questions around the concept of rheumatogenicity and emm type. It has further been postulated that certain GAS emm types (most notably emm3) may be rheumatogenic due to the presence of a specific collagen-binding motif, designated peptide associated with rheumatic fever (PARF), which elicits an immune response to type IV collagen (5,6). To date, however, the presence of the PARF motif has not been systematically assessed in a large collection of GAS strains temporally associated with ARF.…”