Surface proteins of pathogenic streptococci

Streptococcus pyogenes (group A streptococcus) and the group B streptococcus (GBS) are two important human pathogens that cause different types of diseases and express different surface structures implicated in virulence. This thesis focuses on several surface proteins expressed by these pathogens, analyzing the biological function of these proteins and their ability to elicit protective immunity. R28 is a surface protein expressed by some strains of S. pyogenes isolated from cases of puerperal fever, suggesting that R28 may play a role in these infections. Molecular analysis of R28 showed that it is a novel member of a family of extremely repetitive surface proteins first identified through studies of the GBS proteins Rib and alfa. Like the Rib and alfa proteins, R28 was found to be a target for protective antibodies. Moreover, the R28 protein was found to act as an epithelial cell adhesin. Interestingly, the R28 and Rib proteins were shown to cross-react immunologically. This cross-reactivity was found to be surprisingly limited, but sufficient to confer cross-protective immunity between R28-expressing S. pyogenes strains and Rib-expressing GBS strains. Most GBS isolates express a polysaccharide capsule, which is the basis for serological typing of GBS. There are nine capsular serotypes of GBS, one of which, serotype V, has recently become increasingly important in GBS disease. Characterization of serotype V strains allowed identification of two novel GBS surface proteins, Fbs and “Rib-like”, which are targets for protective antibodies and therefore are interesting as possible components in a GBS vaccine. Interestingly, the “Rib-like” protein of type V strains was found to be closely related, if not identical, to the R28 protein of S. pyogenes. Both S. pyogenes and GBS express surface proteins that bind to the Fc part of human IgA. Little is known about the role of these interactions in pathogenesis. The IgA-binding proteins of S. pyogenes are M proteins, which are important virulence factors with antiphagocytic properties. The IgA-binding protein from GBS, the beta protein, is unrelated to the IgA-binding proteins from S. pyogenes. The binding site in IgA for the different streptococcal proteins was mapped to two hydrophobic loops in the Fc interdomain region. This region is also used by the human IgA-receptor CD89, an important mediator of IgA effector functions. In agreement with this result, the IgA-binding streptococcal proteins were found to inhibit binding of IgA to CD89. Thus, unrelated IgA-binding proteins from S. pyogenes and GBS bind the same region in IgA-Fc and may inhibit IgA effector function. The IgA-binding beta protein of GBS was found to contain a separate binding region for human factor H (FH), a plasma protein that regulates complement activation. Bacteria-bound FH retains its regulatory function, indicating that beta-expressing GBS may use FH to downregulate complement deposition and thereby inhibit phagocytosis.