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Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37.

Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, Davidson DJ, Donis RO - PLoS ONE (2011)

Bottom Line: Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation.The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir.These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.

View Article: PubMed Central - PubMed

Affiliation: Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

ABSTRACT
The extensive world-wide morbidity and mortality caused by influenza A viruses highlights the need for new insights into the host immune response and novel treatment approaches. Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation. Cathelicidins have immunomodulatory and anti-viral effects, but their impact on influenza virus infection has not been previously assessed. We therefore evaluated the effect of cathelicidin peptides on disease caused by influenza A virus in mice. The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir. In vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.

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Related in: MedlinePlus

Cathelicidins Mediate Changes in Lung Cytokine Concentrations Following Influenza Virus Infection.Groups of 5 mice were infected with 10 MLD50 of A/PR/8/34 influenza virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), or LL-37 peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and concentration of the indicated cytokines in the bronchoalveolar lavage (BAL) fluid were measured by BioPlex assay. Figures show mean values ± SEM. Statistical analysis was performed using an two-way analysis of variance (ANOVA) (*P≤0.05).
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pone-0025333-g003: Cathelicidins Mediate Changes in Lung Cytokine Concentrations Following Influenza Virus Infection.Groups of 5 mice were infected with 10 MLD50 of A/PR/8/34 influenza virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), or LL-37 peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and concentration of the indicated cytokines in the bronchoalveolar lavage (BAL) fluid were measured by BioPlex assay. Figures show mean values ± SEM. Statistical analysis was performed using an two-way analysis of variance (ANOVA) (*P≤0.05).

Mentions: Cathelicidins have been shown to elicit a number of protective mechanisms in host defense against infection. To determine whether LL-37 might be protecting against influenza infection by modulating the inflammatory response in the lung, a number of cytokines in the bronchoalveolar lavage (BAL) fluid of mice were assessed using a BioPlex assay. Groups of 5 mice were treated with nebulized LL-37 or with saline for 1 day prior to and 2 days after infection with A/PR/8/34 (H1N1). Other groups were not infected and received either LL-37 only or saline only. After PR/8 infection, a number of inflammatory cytokines were found to be increased in the BAL fluid of control infected mice. Significant (p≤0.05) increases of IL-1β, GM-CSF, KC and RANTES were observed in the BAL fluid three days after infection. Treatment with LL-37 did not significantly alter cytokine concentrations in the absence of influenza virus infection. However, in infected mice treated with LL-37 the BAL fluid concentrations of IL-1β, GM-CSF, KC and RANTES were found to be unchanged compared with uninfected controls, and IL-1β and GM-CSF were significantly lower (p≤0.05) than in PR/8 infected control animals. Mice infected with PR/8 also showed a non-significant increase in the BAL fluid concentration of MIP-1α compared to naïve untreated animals (Figure 3E) and this increase was ameliorated when mice were nebulized with LL-37.


Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37.

Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, Davidson DJ, Donis RO - PLoS ONE (2011)

Cathelicidins Mediate Changes in Lung Cytokine Concentrations Following Influenza Virus Infection.Groups of 5 mice were infected with 10 MLD50 of A/PR/8/34 influenza virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), or LL-37 peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and concentration of the indicated cytokines in the bronchoalveolar lavage (BAL) fluid were measured by BioPlex assay. Figures show mean values ± SEM. Statistical analysis was performed using an two-way analysis of variance (ANOVA) (*P≤0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198734&req=5

pone-0025333-g003: Cathelicidins Mediate Changes in Lung Cytokine Concentrations Following Influenza Virus Infection.Groups of 5 mice were infected with 10 MLD50 of A/PR/8/34 influenza virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), or LL-37 peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and concentration of the indicated cytokines in the bronchoalveolar lavage (BAL) fluid were measured by BioPlex assay. Figures show mean values ± SEM. Statistical analysis was performed using an two-way analysis of variance (ANOVA) (*P≤0.05).
Mentions: Cathelicidins have been shown to elicit a number of protective mechanisms in host defense against infection. To determine whether LL-37 might be protecting against influenza infection by modulating the inflammatory response in the lung, a number of cytokines in the bronchoalveolar lavage (BAL) fluid of mice were assessed using a BioPlex assay. Groups of 5 mice were treated with nebulized LL-37 or with saline for 1 day prior to and 2 days after infection with A/PR/8/34 (H1N1). Other groups were not infected and received either LL-37 only or saline only. After PR/8 infection, a number of inflammatory cytokines were found to be increased in the BAL fluid of control infected mice. Significant (p≤0.05) increases of IL-1β, GM-CSF, KC and RANTES were observed in the BAL fluid three days after infection. Treatment with LL-37 did not significantly alter cytokine concentrations in the absence of influenza virus infection. However, in infected mice treated with LL-37 the BAL fluid concentrations of IL-1β, GM-CSF, KC and RANTES were found to be unchanged compared with uninfected controls, and IL-1β and GM-CSF were significantly lower (p≤0.05) than in PR/8 infected control animals. Mice infected with PR/8 also showed a non-significant increase in the BAL fluid concentration of MIP-1α compared to naïve untreated animals (Figure 3E) and this increase was ameliorated when mice were nebulized with LL-37.

Bottom Line: Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation.The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir.These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.

View Article: PubMed Central - PubMed

Affiliation: Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

ABSTRACT
The extensive world-wide morbidity and mortality caused by influenza A viruses highlights the need for new insights into the host immune response and novel treatment approaches. Cationic Host Defense Peptides (CHDP, also known as antimicrobial peptides), which include cathelicidins and defensins, are key components of the innate immune system that are upregulated during infection and inflammation. Cathelicidins have immunomodulatory and anti-viral effects, but their impact on influenza virus infection has not been previously assessed. We therefore evaluated the effect of cathelicidin peptides on disease caused by influenza A virus in mice. The human cathelicidin, LL-37, and the murine cathelicidin, mCRAMP, demonstrated significant anti-viral activity in vivo, reducing disease severity and viral replication in infected mice to a similar extent as the well-characterized influenza virus-specific antiviral drug zanamivir. In vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.

Show MeSH
Related in: MedlinePlus