LL-37 Peptide Fights EV71 Virus by Boosting Host Defense Protein
Background
The LL-37 peptide, a 37-amino acid human-derived antimicrobial peptide, has shown promise in clinical settings, previously shortening the negative conversion time for the Omicron BA.5.1.3 variant of SARS-CoV-2. However, its broader antiviral mechanisms, especially against non-enveloped viruses, remained less understood. This study aimed to uncover the specific host-directed pathways through which LL-37 inhibits infection by Enterovirus 71 (EV71), a common non-enveloped virus responsible for hand, foot, and mouth disease.
Study Design
Results
LL-37 treatment dose-dependently reduced EV71 viral RNA abundance, suppressed virus-encoded protein expression, and decreased infectious titers, indicating its potent antiviral activity. Crucially, LL-37 was found to act predominantly at a post-entry stage of the viral life cycle. Transcriptomic analysis revealed that the Stac (SH3 and cysteine-rich domain protein) gene was uniquely upregulated by LL-37, irrespective of EV71 infection. Silencing Stac using shRNA significantly enhanced EV71 infection, while Stac overexpression markedly reduced it, confirming Stac's critical role in host defense. Furthermore, the study demonstrated that LL-37 activates the EGFR-ERK signaling pathway, leading to a time-dependent upregulation of Stac expression. LL-37 combats EV71 infection by activating the EGFR-ERK signaling pathway, which in turn upregulates the host defense protein Stac.
Why It Matters
This research uncovers a novel host-directed mechanism by which LL-37 exerts its antiviral effects, moving beyond direct viral targeting to modulating the host's own defenses. By identifying the EGFR-ERK-Stac axis, the study provides a deeper understanding of LL-37's broad-spectrum antiviral potential. This mechanism suggests that LL-37 could be a promising candidate for therapeutic use against a range of non-enveloped viral diseases, offering a new strategy to combat infections that lack specific treatments. Future steps should involve in vivo studies and potentially Phase I/II human trials to evaluate its efficacy and safety in clinical settings.