Membrane cofactor protein (MCP, CD46) binding to clinical isolates of Streptococcus pyogenes: binding to M type 18 strains is independent of Emm or Enn proteins.

The complement regulatory protein CD46 (MCP, membrane cofactor protein) is used as a cell receptor by a number of bacterial and viral pathogens, including Streptococcus pyogenes (Group A Streptococci). The highly variable M (Emm) proteins are virulence factors of S. pyogenes, and Emm proteins of serotypes 5, 6 or 22 are able of binding to CD46, thus mediating the binding of Streptococci to human cells. In this work, using a soluble construction encompassing the extracellular domain of human CD46, we have analyzed its binding to clinical isolates of S. pyogenes, including isolates of the M types 1, 3 and 18 that are frequently found in invasive infections or rheumatic fever. Our data show a strong binding of CD46 to bacteria of M types 1, 3, 8, 18, 24, 28, 29, 31 and 78; weak binding to M6 and M29 and no binding to M types 11, 12, M27 or M30. Surprisingly, CD46 bound to isogenic mutants of one clinical M18 isolate lacking the Emm protein or Emm and the Emm-related protein Enn, regardless of having capsule or not. In addition, these isogenic mutants bound to keratinocytes in a CD46-dependent manner, confirming the role of CD46 as one of the cell receptors for Group A Streptococci. Furthermore, CD46 did not bind to a recombinant Emm 18 construct, confirming that Emm is not involved in CD46 binding to M18 bacteria. Emm-dependent and -independent CD46 binding of clinical isolates of Streptococci confirms the importance of CD46 as a cell target that might confer pathogens some biological advantages over the host.