Background: The surface M protein is Group A Streptococcus (GAS) major virulence factor that enables immune escape by binding to several serum proteins. It is also the main current vaccine candidate. Despite similarities to M, M-like proteins (Mrp and Enn) have been overlooked. Their predicted binding motifs suggest they may share binding partners with M such as fibrinogen or C4BP indicating functional redundancy which could lead to vaccine escape. In this study, we investigate how these 3 proteins work together in GAS virulence.
Methods and Results: Mass spectrometry analysis after co-purification in human serum revealed that M and M-like proteins share a lot of host binding partners, in favor of the redundancy theory. Knock-out mutants of emm, enn and mrp in different strains demonstrated, by whole cell binding experiments, that each of the 3 proteins have specific roles in host proteins interaction. Their binding function were also correlated with their role in human blood survival. Moreover, RT-qPCR experiments showed that M and M-like genes are differentially expressed in human blood, suggesting that in addition to Mga, their expression depends on other regulators responsive to environmental changes. Our data indicate that M and M-like proteins, despite their apparent redundant binding capacity, are important virulence factors that could be required at specific time-point/site of infection.
Conclusion: This work raises the importance of studying M and M-like proteins as a single, tripartite, virulence system rather than isolated factors. Understanding their regulation and cooperation is crucial for unraveling GAS virulence and designing effective vaccines.