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

What the researchers found

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.

Why it matters

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.

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

This is a mechanistic in vitro study using a single cell line. The experimental design is rigorous with appropriate controls and pharmacological validation, but findings have not been confirmed in primary cells or animal models.

When this study was published

Published in 2025, this is very current and adds to the rapidly growing understanding of LL-37's immunomodulatory roles beyond direct antimicrobial activity.

The bigger picture

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.

Questions still open

• Does LL-37 enhance interferon production in response to other respiratory viruses like influenza or RSV through the same calcium mechanism?
• Are people with lower LL-37 levels in their airways more susceptible to rhinovirus infections?
• Could exogenous LL-37 or LL-37-derived peptides be developed as an inhaled antiviral treatment?

Common questions

Read the original research

Antimicrobial peptide LL-37 increases rhinovirus-induced interferon β expression in human airway epithelial cells through a Ca2+-dependent mechanism.

Biochemistry and biophysics reports, 43, 102105

Citation

Cerps, Samuel; Ramu, Sangeetha; Gidlöf, Olof; Menzel, Mandy; Swärd, Karl; Uller, Lena; Nilsson, Bengt-Olof. (2025). Antimicrobial peptide LL-37 increases rhinovirus-induced interferon β expression in human airway epithelial cells through a Ca2+-dependent mechanism.. Biochemistry and biophysics reports, 43, 102105. https://doi.org/10.1016/j.bbrep.2025.102105