LL-37 Boosts Your Airway's Antiviral Response to the Common Cold Virus

LL-37 at 4 μM concentration enhanced rhinovirus-induced interferon-beta (IFNβ) expression in BEAS-2B human airway epithelial cells and reduced viral load. This enhancement did not involve upregulation of classical viral sensors (TLR3, MDA5, RIG-I). Instead, the effect was dependent on endosomal acidification (blocked by chloroquine) and critically required calcium — chelating calcium with EGTA abolished the response. LL-37 directly increased intracellular calcium concentration, and mimicking this calcium rise with the ionophore A23187 replicated the IFNβ enhancement, confirming that calcium is the key mediator.

Human airway epithelial cells (BEAS-2B cell line) were infected with rhinovirus in the presence or absence of LL-37 (4 μM). IFNβ transcript levels were measured, along with viral load. Receptor expression (TLR3, MDA5, RIG-I) was assessed. Pharmacological inhibitors were used to probe mechanisms: chloroquine for endosomal acidification, EGTA for calcium chelation. Intracellular calcium was measured using the Fluo-4 AM fluorescent indicator. The calcium ionophore A23187 was used to confirm the calcium-dependent mechanism.

LL-37 was already known to kill bacteria and viruses directly, but this study reveals an additional indirect mechanism: it boosts the cell's own antiviral alarm system (interferon production) through a calcium-dependent pathway. This adds a new dimension to how the body's innate immune peptides fight respiratory infections and could inform therapeutic strategies for enhancing antiviral defenses in the airways.

LL-37 is the only human cathelicidin and plays multiple roles in innate immunity. This study expands understanding of how it contributes to antiviral defense beyond direct pathogen killing — by amplifying the interferon response through calcium signaling. As respiratory viruses remain a major health burden, understanding these natural defense mechanisms could lead to new approaches for boosting airway immunity, particularly in people with LL-37 deficiency.

The study used a single immortalized cell line (BEAS-2B), which may not fully represent primary airway epithelial cell behavior. All experiments were conducted in vitro with no animal or human data. Only one rhinovirus strain was tested. The LL-37 concentration used (4 μM) may or may not reflect physiological concentrations in the airways during infection. Long-term effects and potential cytotoxicity at this concentration were not assessed.