Oral Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

LL-37 cleavage by the Group A streptococcus CXC chemokine protease eliminates its immunomodulatory activities thus promoting invasive infection (#59)

Debabrata Biswas 1 , Poornima Ambalavanan 1 , Nadia Suray Tan 2 , Veronique Angeli 2 , Emanuel Hanski 1 3
  1. NUS-HUJ Cellular & Molecular Mechanisms of Inflammation Programme, Department of Microbiology and Immunology, National University of Singapore, Singapore
  2. Immunology Programme, Department of Microbiology and Immunology, National University of Singapore, Singapore
  3. Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

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.