Abstract
The non-immune binding of immunoglobulins by bacteria is thought to contribute to the pathogenesis of infections. M-related proteins (Mrp) are group A streptococcal (GAS) receptors for immunoglobulins, but it is not known if this binding has any impact on virulence. To further investigate the binding of immunoglobulins to Mrp, we engineered mutants of an M type 4 strain of GAS by inactivating the genes for mrp, emm, enn, sof, and sfbX and tested these mutants in IgG-binding assays. Inactivation of mrp dramatically decreased the binding of human IgG, whereas inactivation of emm, enn, sof, and sfbx had only minor effects, indicating that Mrp is a major IgG-binding protein. Binding of human immunoglobulins to a purified, recombinant form of Mrp indicated that it selectively binds to the Fc domain of human IgG, but not IgA or IgM and that it preferentially bound subclasses IgG1>IgG4>IgG2>IgG3. Recombinant proteins encompassing different regions of Mrp were engineered and used to map its IgG-binding domain to its A-repeat region and a recombinant protein with 3 A-repeats was a better inhibitor of IgG binding than one with a single A-repeat. A GAS mutant expressing Mrp with an in-frame deletion of DNA encoding the A-repeats had a dramatically reduced ability to bind human IgG and to grow in human blood. Mrp exhibited host specificity in binding IgG; human IgG was the best inhibitor of the binding of IgG followed by pig, horse, monkey, and rabbit IgG. IgG from goat, mouse, rat, cow, donkey, chicken, and guinea pig were poor inhibitors of binding. These findings indicate that Mrp preferentially binds human IgG and that this binding contributes to the ability of GAS to resist phagocytosis and may be a factor in the restriction of GAS infections to the human host.
Highlights
The group A streptococcus, Streptococcus pyogenes, is an important human pathogen that is estimated to be the ninth leading cause of deaths due to microbial infections worldwide [1]
Purified Mrelated protein (Mrp) has been shown to bind human IgG, but it was not known if Mrp is the major surface protein that binds IgG or if this binding has any role in resistance to phagocytosis in human blood
We present our findings indicating that the Fc-mediated binding of human IgG to the A-repeats of Mrp does confer resistance to phagocytosis and enhances growth of S. pyogenes in human blood
Summary
The group A streptococcus, Streptococcus pyogenes, is an important human pathogen that is estimated to be the ninth leading cause of deaths due to microbial infections worldwide [1]. Members of the M protein family are key virulence factors that contribute to the pathogenesis of S. pyogenes infections and their binding of blood proteins, such as complement regulatory proteins, plasminogen, albumin, fibrinogen, and immunoglobulins, is thought to contribute to pathogenesis [2,3,4,5,6,7,8,9,10,11,12,13,14]. The M protein family is composed of M protein (Emm), Mrelated protein (Mrp), and an M-like protein (Enn), which are part of the Mga regulon (Figure 1). Emm binds fibrinogen in pattern A serotypes whereas Mrp is the major fibrinogen-binding protein in pattern D and E serotypes [3,5,7,11]
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