Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein

Cunningham, M.W.; Antone, S.M.; Smart, M.; Liu, R.; Kosanke, S.

Infection and Immunity 65(9): 3913-3923


ISSN/ISBN: 0019-9567
PMID: 9284171
Accession: 009038933

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The group A streptococcal M protein is an important virulence determinant eliciting protective and autoimmune responses against the streptococcus and cardiac myosin, respectively. In this report, the major human cardiac myosin-cross-reactive T-cell epitopes of MS protein are identified and localized to myosin-like repeats within the MS molecule. BALB/c mice were immunized with human cardiac myosin, and the dominant myosin-cross-reactive T-cell epitopes of MS protein were identified with a panel of 23 overlapping peptides spanning the A, B, and C repeat regions of MS protein. Human cardiac myosin-cross-reactive T-cell epitopes of MS protein were localized to several sequences in the MS peptides NT4 (GLKTENEGLKTENEGLKTE), NT5 (KKEHEAENDKLKQQRDTL), B1B2 (VKDKEAKEQENKETIGTL), B2 (TIGTLKKILDETVKDKIA), B3A (IGTLKKILDETVKDKLAK), and C3 (KGLRRDLDASREAKKQ). The NT4 repeated sequence LKTEN was highly homologous with a site conserved in cardiac myosins, the B repeat region peptides were 47% homologous to human cardiac myosin amino acid sequence, and the C3 sequence RRDL was identical to a highly conserved site in skeletal and cardiac myosins. Immunization of BALB/c mice with each of the overlapping MS peptides revealed myosin-cross-reactive B-cell epitopes throughout the A and C repeat regions and one major epitope in the B repeat region containing the previously reported Gln-Lys-Ser-Lys-Gln (QKSKQ) epitope. The data suggest that the MS peptides elicited higher antibody titers to cardiac myosin than to skeletal myosin and that several sites in the A and B repeat regions of MS protein induced myocardial inflammatory infiltrates.