Study summary · research use only
LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study combining biochemical binding assays and a mouse model, the authors examined how the human cathelicidin peptide LL-37 interacts with SARS-CoV-2 spike protein. LL-37 was reported to predominantly bind the S2 subunit of spike, occupying sites where TMPRSS2 typically binds, and to impede TMPRSS2-mediated priming at the S2' site and subsequent membrane fusion. The N764K mutation within the S2 subunit of Omicron variants was reported to significantly reduce binding affinity for LL-37, diminishing its inhibitory effects on membrane fusion. The abstract also reports that in mice, LL-37 enhanced early humoral immune responses against SARS-CoV-2 spike but not against Omicron BA.4/5 spike.
Abstract
Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.
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