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J. Biol. Chem., Vol. 282, Issue 26, 18686-18693, June 29, 2007

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Identification of a Streptococcal Octapeptide Motif Involved in Acute Rheumatic Fever^*

Katrin Dinkla¹, D. Patric Nitsche-Schmitz¹, Vanessa Barroso, Silvana Reissmann, Helena M. Johansson, Inga-Maria Frick, Manfred Rohde, and Gursharan S. Chhatwal²

From the Department of Microbial Pathogenesis, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany and Department of Clinical Sciences, Lund University, 22184 Lund, Sweden

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.

Received for publication, February 5, 2007 , and in revised form, March 28, 2007.

^* This work was supported by the Marie Curie Early Stage Research Training of the European Community's Sixth Framework Programme under Contract MEST-CT-2004-504990 and by Swedish Research Council Project 7480. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Microbial Pathogenesis, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. Tel.: 49-531-6181-4400; Fax: 49-531-6181-4499; E-mail: gsc{at}helmholtz-hzi.de.

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