M1 protein from streptococcus pyogenes induces nitric oxide-mediated vascular hyporesponsiveness to phenylephrine: involvement of toll-like receptor activation.

Streptococcus pyogenes carrying M1 protein causes the severe and increasingly prevalent streptococcal toxic shock syndrome and necrotizing fasciitis. M1 protein is an important virulence factor of S. pyogenes and induces an inflammatory response in human monocytes. We wanted to investigate if purified M1 protein in solution could induce vascular NO production leading to vasopressor hyporesponsiveness. Rat aortic segments were incubated with M1 protein or LPS in vitro. M1 protein (10 microg mL) and LPS (1 ng mL) to a similar extent induced NO production and hyporesponsiveness to the vasoconstrictor phenylephrine. Immunogold electron microscopy demonstrated that M1 protein binds to Toll-like receptor 2 (TLR2) as well as TLR4 in mouse aorta but only to TLR2 in human omental artery. Incubation with M1 protein caused a reduction in the contractile response to phenylephrine in aortic segments from wild-type and TLR2-knockout but not from TLR4-knockout mice. In conclusion, M1 protein causes vascular NO production leading to hyporesponsiveness to vasopressors via a mechanism involving TLR, but the subtypes may be species dependent. M1 protein could contribute to the circulatory disturbances accompanying severe invasive streptococcal infections.