Abstract
The surface-localized M protein of Streptococcus pyogenes is a major virulence factor that inhibits phagocytosis, as determined ex vivo. Because little is known about the role of M protein in vivo we analyzed the contribution of different M protein regions to virulence, using the fibrinogen (Fg)-binding M5 protein and a mouse model of acute invasive infection. This model was suitable, because M5 is required for mouse virulence and binds mouse and human Fg equally well, as shown here. Mixed infection experiments with wild type bacteria demonstrated that mutants lacking the N-terminal hypervariable region (HVR) or the Fg-binding B-repeat region were strongly attenuated, while a mutant lacking the conserved C-repeats was only slightly attenuated. Because the HVR of M5 is not required for phagocytosis resistance, our data imply that this HVR plays a major but unknown role during acute infection. The B-repeat region is required for phagocytosis resistance and specifically binds Fg, suggesting that it promotes virulence by binding Fg. However, B-repeat mutants were attenuated even in Fg-deficient mice, implying that the B-repeats may have a second function, in addition to Fg-binding. These data demonstrate that two distinct M5 regions, including the HVR, are essential to virulence during the early stages of an infection. In particular, our data provide the first in vivo evidence that the HVR of an M protein plays a major role in virulence, focusing interest on the molecular role of this region.
Highlights
A surface protein of a bacterial pathogen qualifies as a virulence factor if a mutant lacking this protein is attenuated in an animal infection model
The Crepeat region binds albumin [25,26,27], and promotes binding to CD46, a surface-localized complement regulator present on all human cells [8,11]. It is not known whether M5 and other M proteins bind CD46 of mouse origin, but even if this were the case, the limited tissue distribution of CD46 in normal mice [28] makes it unlikely that the interaction would be of relevance in the mouse model
We used a mouse model to analyze the contribution to virulence of different regions in the S. pyogenes M5 protein
Summary
A surface protein of a bacterial pathogen qualifies as a virulence factor if a mutant lacking this protein is attenuated in an animal infection model. Many bacterial proteins fulfill this criterion, little is known about the contribution to virulence of different regions within a protein. We study this problem for the M protein of Streptococcus pyogenes (group A streptococcus), a major human pathogen [1]. The best known property of this protein is its ability to inhibit phagocytosis under nonimmune conditions, i.e. in the absence of opsonizing antibodies. Evidence for this property was first obtained in classical ex vivo studies employing whole human blood [6,7]. Little is known about the function of M protein in vivo
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