LL-37 and Respiratory Viruses: Antiviral Evidence

Defensins Against Influenza and COVID

Comparable to zanamivir

In a mouse influenza model, LL-37 reduced viral replication and disease severity to a similar extent as the pharmaceutical antiviral zanamivir (Tamiflu-class drug).

Barlow et al., PLoS ONE, 2011

Barlow et al., PLoS ONE, 2011

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Your lungs produce their own antiviral peptides. The most studied is LL-37, a 37-amino acid fragment of the cathelicidin protein hCAP-18, which is expressed by airway epithelial cells, neutrophils, and macrophages in the respiratory tract.^[1] In laboratory studies, LL-37 directly damages the envelopes of influenza virus, respiratory syncytial virus (RSV), and rhinovirus. In a mouse influenza model, it reduced viral replication and disease severity to a degree comparable to zanamivir, a pharmaceutical antiviral.^[2] For the broader picture of how peptides defend the airways, see the pillar article on defensins and airway peptide defense.

These findings position LL-37 as one of the best-characterized antiviral peptides in innate immunity. The evidence is strong in cell culture and animal models, with some human correlational data. What is absent is any clinical trial testing LL-37 as a therapeutic antiviral in human respiratory infection.

What LL-37 is and where it comes from

LL-37 is the only cathelicidin antimicrobial peptide in humans. It is produced as the C-terminal fragment of the 18 kDa precursor protein hCAP-18 (human cationic antimicrobial protein 18), which is cleaved by proteinase 3 to release the active LL-37 peptide. The name derives from the two leucine residues at its N-terminus and its 37-amino acid length.^[3]

In the lungs, LL-37 is expressed by airway epithelial cells, alveolar macrophages, and neutrophils. Expression increases during infection and inflammation, making it part of the innate immune response rather than a constitutively present barrier.^[1] Vitamin D is a major regulator of cathelicidin expression, which has generated interest in the relationship between vitamin D status and respiratory infection susceptibility. The article on vitamin D and LL-37 covers this connection in detail.

Beyond its antimicrobial role, LL-37 functions as a multifunctional immunomodulator. A 2016 review catalogued its activities: chemotaxis of immune cells, modulation of dendritic cell differentiation, angiogenesis promotion, wound healing stimulation, and both pro-inflammatory and anti-inflammatory effects depending on context.^[4] The article on LL-37's dual inflammatory role explores these paradoxical effects. This complexity means LL-37's antiviral activity in the lungs cannot be separated from its broader immunomodulatory functions.

The influenza evidence

The most rigorous antiviral data for LL-37 comes from influenza studies.

Barlow et al. (2011) tested LL-37 and its murine equivalent mCRAMP against influenza A virus (IAV) in both cell culture and a mouse infection model.^[2] In vitro, LL-37 inhibited IAV infectivity in a dose-dependent manner when the peptide was pre-incubated with virus before adding to cells. This pre-incubation requirement is significant: it indicates the peptide acts on the virus directly rather than on the host cells. In the mouse model, intranasal administration of LL-37 reduced viral titers in the lungs, decreased disease severity, and lowered concentrations of pro-inflammatory cytokines compared to infected but untreated animals. The magnitude of protection was comparable to zanamivir, a neuraminidase inhibitor that represents the standard of care for influenza treatment.

Tripathi et al. (2013) dissected the mechanism further. Their study showed that LL-37 inhibits IAV through a pathway distinct from surfactant protein D (SP-D) and defensins, both of which also have anti-influenza activity.^[5] While SP-D works by binding to influenza hemagglutinin and blocking viral attachment, LL-37 directly disrupts the viral envelope. Electron microscopy showed visible morphological damage to viral particles after LL-37 exposure. The peptide also inhibited both seasonal and pandemic H1N1 strains, though potency varied between strains.

This dual mechanism (direct virion damage plus immunomodulation) distinguishes cathelicidins from most pharmaceutical antivirals, which typically target a single viral protein. However, the same breadth that makes LL-37 interesting also makes it harder to develop as a drug, since its effects on the host immune system introduce complexity that narrow-spectrum antivirals avoid.

RSV: from cell culture to human correlations

Respiratory syncytial virus is the leading cause of lower respiratory tract infection in infants and young children. LL-37 has shown activity against RSV across multiple experimental systems.

In cell culture studies, LL-37 prevented RSV-induced cell death in epithelial cells, reduced the production of new infectious viral particles, and diminished the spread of infection between cells. The mechanism, as with influenza, involves direct damage to the viral envelope. LL-37's cationic charge allows it to interact with the negatively charged lipid components of viral membranes, disrupting their integrity.

The most compelling RSV data comes from a human challenge study. In healthy adult volunteers experimentally infected with RSV, higher nasal levels of LL-37 at baseline were associated with protection against infection. This is correlational, not causal, but it provides the strongest link between endogenous cathelicidin levels and viral susceptibility in humans.

A 2010 review by Bucki et al. placed the RSV findings in context, noting that LL-37's antiviral activity against enveloped viruses is a logical extension of its ability to disrupt bacterial membranes through similar electrostatic and hydrophobic interactions.^[6] However, the review also noted that LL-37 concentrations needed for antiviral effects in vitro (typically 5-25 micromolar) are higher than typical physiological concentrations in airway surface liquid, raising questions about whether endogenous LL-37 alone reaches sufficient local concentrations during infection.

Rhinovirus: the interferon connection

Rhinoviruses, the most common cause of the common cold, are non-enveloped viruses. Since LL-37's primary antiviral mechanism involves envelope disruption, rhinovirus resistance would be expected. Surprisingly, LL-37 still shows activity, but through a different mechanism.

A 2025 study by Cerps et al. demonstrated that LL-37 increases rhinovirus-induced interferon-beta expression in human airway epithelial cells through a calcium-dependent signaling pathway.^[7] Rather than directly destroying rhinovirus particles, LL-37 appears to enhance the host cell's antiviral response. Interferon-beta is a cytokine that activates antiviral gene programs in neighboring cells, establishing a defensive perimeter around infected tissue.

This is a fundamentally different mechanism from the envelope disruption seen with influenza and RSV. It means LL-37's antiviral repertoire extends beyond enveloped viruses, but through indirect immunomodulatory pathways rather than direct killing. The practical implication is that LL-37-based therapies, if they are ever developed, might need different dosing strategies for enveloped versus non-enveloped respiratory viruses.

SARS-CoV-2: a different target

The COVID-19 pandemic generated interest in whether endogenous antimicrobial peptides might provide some protection against SARS-CoV-2. The virus is enveloped, making it theoretically susceptible to LL-37-mediated membrane disruption.

Bhatt et al. (2023) showed that niacinamide (vitamin B3) enhanced cathelicidin-mediated SARS-CoV-2 membrane disruption in vitro.^[8] Separately, computational and in vitro studies have suggested that LL-37 can bind to the ACE-2 receptor binding domain used by SARS-CoV-2 for cell entry, potentially blocking viral attachment through a steric interference mechanism.

These findings are preliminary. No clinical study has tested whether LL-37 levels, vitamin D-induced cathelicidin expression, or exogenous LL-37 administration affects COVID-19 outcomes. The niacinamide finding is particularly early-stage, based on cell culture data without animal model validation.

When cathelicidins do harm: the neonatal warning

A 2025 study by Rao et al. provided an important counterpoint to the antiviral narrative. In neonatal mice infected with influenza virus, cathelicidin-related antimicrobial peptide (CRAMP, the mouse equivalent of LL-37) was toxic rather than protective.^[9] Neonatal mice with higher CRAMP expression had worse infection outcomes, while CRAMP-deficient neonates fared better.

The likely explanation involves the immunomodulatory effects of cathelicidins. In neonates, whose immune systems are still developing, the pro-inflammatory signaling triggered by cathelicidins may cause more tissue damage than the antiviral activity prevents. This is consistent with the broader pattern in innate immunity: the same molecules that protect adults can harm neonates through excessive inflammation.

This finding has implications for any future therapeutic application. Cathelicidin-based antivirals would need careful dose calibration and patient selection. Boosting LL-37 in the lungs of a healthy adult during influenza season might be beneficial; doing the same in a premature infant with RSV could be harmful.

The broader cathelicidin family

LL-37 is the human representative, but cathelicidins exist across vertebrates. Pashaie et al. (2024) tested cathelicidins from porcine sources against porcine epidemic diarrhea virus (PEDV), demonstrating that the antiviral activity is conserved across species and virus families.^[10] Studies have also identified cathelicidins from sea snakes, elephants, and hedgehogs with antiviral properties against influenza, herpes simplex, and other viruses.

This evolutionary conservation suggests that cathelicidin-mediated antiviral defense is ancient and fundamental, not a peculiarity of human LL-37. For a broader view of how antimicrobial peptides defend the lungs across multiple peptide families, see the dedicated article. It also expands the pool of peptide sequences that could serve as templates for synthetic antiviral drug design. The article on antimicrobial peptides as antibiotic alternatives covers the broader therapeutic potential. For the specific role of beta-defensins in barrier tissues including the lungs, see the dedicated article.

What cathelicidins in COPD tell us

Burkes et al. (2020) found that plasma cathelicidin levels are independently associated with reduced lung function in COPD patients.^[11] This is not antiviral data, but it provides important context. In chronic lung disease, persistent cathelicidin expression may contribute to ongoing inflammation and tissue remodeling rather than protecting against infection. The same peptide that clears an acute virus may worsen a chronic inflammatory condition.

This duality aligns with the broader understanding of LL-37 as context-dependent. The article on how LL-37 activates neutrophils and dendritic cells explores these immune cell interactions. In acute infection, LL-37's recruitment of immune cells is protective. In chronic disease, persistent recruitment drives fibrosis and airway destruction.

Gaps between lab evidence and clinical application

The LL-37 antiviral literature is substantial but has clear boundaries:

What is established. LL-37 directly disrupts enveloped respiratory viruses (influenza, RSV) in cell culture. It reduces viral titers and disease severity in mouse models of influenza. Higher endogenous LL-37 levels correlate with RSV resistance in human challenge studies. These findings are replicated across multiple independent labs.

What is missing. No clinical trial has tested exogenous LL-37 (inhaled, intranasal, or systemic) as an antiviral in human respiratory infection. No pharmacokinetic data exists for inhaled LL-37 in humans. The dose-response relationship between airway LL-37 concentration and antiviral protection has not been defined in humans. No head-to-head comparison with existing antivirals has been conducted in clinical settings.

What is complicated. LL-37's immunomodulatory effects make therapeutic development unpredictable. The same peptide that reduces influenza severity in adult mice worsens outcomes in neonatal mice. Chronic cathelicidin elevation associates with worse lung function in COPD. Any therapeutic application would need to navigate the line between antiviral benefit and inflammatory harm.

A 2010 review by Wu et al. on cathelicidins in tissue repair noted that the gastrointestinal and respiratory tracts share similar patterns of cathelicidin expression and function, suggesting that insights from gut cathelicidin research may inform respiratory applications.^[12]

The Bottom Line

LL-37, the only human cathelicidin, has well-documented antiviral activity against influenza, RSV, and rhinovirus in laboratory studies. It works primarily by disrupting viral envelopes and enhancing interferon responses. Mouse studies show protection comparable to pharmaceutical antivirals. Human correlational data links higher nasal LL-37 to RSV resistance. The translation gap is wide: no clinical trial has tested LL-37 as an antiviral therapy, and the peptide's dual pro-inflammatory and anti-inflammatory effects make therapeutic development complex. Age-specific risks, particularly in neonates, add an additional layer of caution to any clinical application.

Frequently Asked Questions

Does LL-37 kill viruses?

LL-37 disrupts the envelopes of influenza A, RSV, and other enveloped respiratory viruses, preventing them from infecting cells. Electron microscopy shows visible damage to viral particles after LL-37 exposure. For non-enveloped viruses like rhinovirus, LL-37 does not directly kill the virus but instead enhances the host cell's interferon response. In mouse models, LL-37 reduced influenza viral titers comparably to the antiviral drug zanamivir.

Can LL-37 protect against COVID-19?

In vitro studies show that LL-37 can disrupt SARS-CoV-2 envelopes, and niacinamide enhances this effect. Computational studies suggest LL-37 may block the ACE-2 binding site used by the virus for cell entry. No clinical trial has tested whether boosting LL-37 levels protects against COVID-19 in humans. The evidence remains at the cell culture stage.

Does vitamin D increase LL-37 in the lungs?

Vitamin D is the primary transcriptional regulator of cathelicidin expression in humans. When vitamin D binds its receptor in airway epithelial cells, it upregulates hCAP-18 production, which is then cleaved to release LL-37. This pathway has generated the hypothesis that vitamin D deficiency increases respiratory infection susceptibility partly through reduced LL-37 production, though clinical trials testing this have produced mixed results.

Is LL-37 being developed as an antiviral drug?

No inhaled or intranasal LL-37 product is currently in clinical trials for respiratory viral infection. One LL-37-based product has been tested in a clinical trial for wound healing (venous leg ulcers), confirming that the peptide can be safely administered to humans. The antiviral application faces challenges including peptide stability in aerosol form, dose calibration, and the risk of excessive inflammation.

Is LL-37 safe to use in the lungs?

LL-37 is naturally produced in the lungs during infection, so the peptide itself is physiologically normal in airway tissue. The safety concern is not toxicity but dysregulation. In neonatal mice, excess cathelicidin worsened influenza outcomes. In COPD patients, elevated plasma cathelicidin correlates with reduced lung function. These findings suggest that timing, dose, and patient characteristics would determine whether exogenous LL-37 helps or harms.

How does LL-37 compare to defensins for antiviral defense?

LL-37 and defensins both disrupt viral envelopes but through different mechanisms. LL-37 acts primarily through electrostatic interactions with viral lipid membranes, while alpha-defensins and theta-defensins can directly bind viral glycoproteins. LL-37 also has stronger immunomodulatory activity, recruiting and activating immune cells at the infection site. For a comparison of these peptide defense systems, see the pillar article on airway peptide defense.