Severe soft tissue infections caused by Group A streptococci (GAS) are characterized by rapid dissemination of GAS followed by massive necrosis of the infected tissue. The GAS serine protease ScpC (also known as SpyCEP) plays a central role in GAS virulence by cleaving the host CXC-chemokine, interleukin-8 (IL-8) and thus impairing recruitment, activation and formation of neutrophil extracellular traps (NETs).
IL-8 has been the only identified substrate of ScpC. Here, we report that the human cathelicidin anti-microbial peptide, LL-37, also serves as a substrate for ScpC. LL-37 cleavage by ScpC results in the loss of its immunomodulatory activity, namely the ability to recruit neutrophils directly, and to stimulate IL-8 production by skin keratinocytes. These activities seem pertinent to human invasive soft-tissue GAS infections as previous study revealed the coexistence of LL-37 with viable bacteria in soft tissues debrided from human patients. This study hinted that LL-37 does not necessarily act as an anti-microbial peptide but perhaps as immuno-modulator of the innate immune response. The identification of the LL-37 cleavage site by ScpC enabled us to produce LL-37-derived peptides that were resistant to ScpC cleavage and retained their immunomodulatory functions. Using the murine model of human GAS soft tissue infection, we demonstrated that the LL-37 analogs significantly affected the distribution of neutrophils in the infected tissues.