Studies on streptococcal M proteins. Interactions with IgA and human complement regulators

The human pathogenic bacterium <i>Streptococcus pyogenes</i> (group A <i>Streptococcus</i>) expresses several different virulence factors. Of these, the M protein is regarded as one of the most important, because it confers resistance to phagocytosis, allowing the bacterium to multiply in blood. A remarkable property of M proteins is their ability to bind different human plasma proteins, in particular components of the immune system. This property is believed to be of importance for the biological functions of M protein. This thesis describes studies of two such interactions: binding of IgA and binding of regulators of complement activation.

Many M proteins bind to the Fc part of IgA, the major immunoglobulin on mucosal surfaces. The biological role of this binding is not yet known, but the IgA-binding proteins are valuable model systems for studies of IgA. Alignment of the amino acid residue sequences of five different IgA-binding M proteins identified a putative IgA-binding region. Further analysis of one M protein demonstrated that a 29-residue region was necessary and sufficient for IgA-binding. Subsequent work showed that the IgA-binding region can be studied in the form of a synthetic peptide. Indeed, a 50-residue peptide including the IgA-binding region binds IgA with high specificity, and the properties of this peptide indicate that it corresponds to an isolated IgA-binding domain.

An important property of M proteins is the presence of an N-terminal hypervariable region, which probably plays a major role in pathogenesis. However, the function of the hypervariable region has remained unknown. We have found that the hypervariable region of many M proteins specifically binds a ligand, the human complement regulator C4BP. Alignment of the amino acid residue sequences of several C4BP-binding regions did not reveal any identities sufficient to explain the binding of C4BP. Thus, hypervariable regions with highly divergent primary sequences all bind the same ligand, C4BP. This ability to bind C4BP may explain the capacity of these M proteins to confer phagocytosis resistance, since bound C4BP may protect the bacterium against complement attack. However, some M proteins do not bind C4BP. Analysis of two such M proteins demonstrated that their hypervariable regions bind another human complement regulator, FHL-1. Thus, the studies with C4BP and FHL-1 made it possible to attribute a specific function to the hypervariable region of many M proteins: the binding of a human complement regulator.