Streptococcus pyogenes (group A streptococcus) is a major and strict human pathogen. It contains a surface-anchored M protein that is essential for virulence and colonization, by inhibiting phagocytosis ex-vivo. Because little is known about the role of Streptococcus pyogenes M protein in vivo, Waldemarsson et al 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. The Streptococcus pyogenes M5 protein can be divided into three distinct regions: the N-terminal hypervariable region (HVR), the B-repeat region and the C-repeat region.

In a first step, mice were infected with wild type Streptococcus pyogenes, containing intact M5 protein, or with a mutant lacking the entire M5 protein; results demonstrated that all mice infected with wild type Streptococcus pyogenes succumbed to infection, whereas all mice in the group infected with the mutant survived. In a second step, mice were infected with mutant strains of Streptococcus pyogenes and results clearly showed that mutants lacking the HVR or the B-repeat region were strongly attenuated, while a Streptococcus pyogenes mutant lacking the conserved C-repeats was only slightly attenuated.

Because the HVR of Streptococcus pyogenes M5 is not required for phagocytosis resistance, their data imply that this HVR plays a major but unknown role during acute infection. The B-repeat region of Streptococcus pyogenes is required for phagocytosis resistance and specifically binds Fg, suggesting that it promotes virulence by binding Fg.

According to Waldemarsson et al, “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.”