Rheumatic fever is a severe inflammatory disease that affects the heart, brain, and connective tissues. A substantial body of evidence indicates that rheumatic fever is an autoimmune disease triggered by Streptococcus pyogenes (Group A Strep) infection. While the incidence of rheumatic fever has declined in the US over the last several decades for reasons that are not entirely clear, the potential of rheumatic fever being triggered by streptococcal vaccines has limited the development of such vaccines. A more thorough understanding for the basis of antibody cross-reactivity between streptococcal and self-antigens is required for making progress on streptococcal vaccines. One of the dominant hypotheses for antibody cross-reactivity centers on M proteins, which are major streptococcal antigens and virulence factors. M proteins are predicted to form dimeric ?-helical coiled-coils and hypothesized to elicit cross-reactive antibodies through molecular mimicry of self proteins having similar coiled-coil structures, such as laminin, myosin, and tropomyosin. However, no atomic-resolution structure of any M protein exists to evaluate this hypothesis. Furthermore, protein structure modeling of M proteins is problematic due to the non-canonical nature of their coiled-coil sequences. The major impediment to evaluating the molecular mimicry hypothesis has been difficulty in crystallizing M proteins. We have overcome this problem and have obtained crystals that diffract to ~2.9 ? resolution. Our first specific aim is to complete the structure determination of a functional, physiologically produced fragment of M1, a highly prevalent M protein genotype associated with rheumatic fever and invasive bacterial infections. A portion of this M1 fragment constitutes part of a promising 26-valent streptococcal vaccine currently in clinical trials. Our second specific aim is to determine the basis for recognition of M1 by cross-reactive antibodies: We propose to determine the structure of M1 in complex with a Fab fragment from a cross-reactive antibody. Detailed knowledge of potential molecular mimicry and cross-reactivity in M1 protein will be applicable to considerations of safety and efficacy in streptococcal vaccines. ? ? A major problem in developing vaccines to combat infection by Streptococcus pyogenes is the possibility that such vaccines will bring about rheumatic fever, which is an autoimmune condition affecting the heart, brain, and joints. We seek to understand the basis for such autoimmune reactions more thoroughly by studying the structure of M1 protein, a major streptococcal antigen that has been hypothesized to resemble certain human proteins and therefore to elicit autoimmune antibodies. The results from our studies are likely to indicate which features of M1 elicit such antibodies, and this information may be applicable to the design of safe and effective streptococcal vaccines. ? ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-A (90))
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Rubin, Fran A
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University of California San Diego
Schools of Arts and Sciences
La Jolla
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Macheboeuf, Pauline; Buffalo, Cosmo; Fu, Chi-yu et al. (2011) Streptococcal M1 protein constructs a pathological host fibrinogen network. Nature 472:64-8
Lauth, Xavier; von Köckritz-Blickwede, Maren; McNamara, Case W et al. (2009) M1 protein allows Group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J Innate Immun 1:202-14
McNamara, Case; Zinkernagel, Annelies S; Macheboeuf, Pauline et al. (2008) Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence. Science 319:1405-8