Sign In

LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection

Group A Streptococcus (GAS) causes a wide range of human diseases, including the life-threatening infection necrotizing fasciitis (NF), coined by the public as a "flesh-eating disease." Despite prompt treatments and surgical intervention, NF mortality ranges between 25 to 45 %. There is no effective vaccine against GAS diseases. These facts stress the urgent need for new approaches to control GAS invasive infections. The research groups in Singapore and Israel led by Emanuel Hanski challenged 20 years commonly accepted concept that the human antimicrobial peptide LL-37 acts by killing invasive GAS. (Singapore-"SHARE" The Singapore-Hebrew University Alliance for Research and Enterprise; Israel-the Hebrew University Hadassah Medical School Website). Using a mouse model of human NF, the groups showed that GAS uses a unique protease to cleave LL-37. The cleavage obliterated P2X7 and EGF host receptors' activation by LL-37 but maintained its killing activity. Newly designed and synthesized non-cleavable LL-37 analogs activated those receptors and protected against GAS infection. Antagonists of these host receptors annulled their protectivity. This work provides an exquisite understanding of the GAS-human interactions during the infection that paves the way to design precise and effective therapies against GAS diseases, some of which are very difficult to treat.
graphical abstract
Prof. Emanuel Hanski and Cell logo