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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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LL-37 Protects Mice Against Influenza Virus Disease.(A,B) Groups of 5 mice were inoculated with 10 MLD50 of A/Puerto Rico/8/1934 influenza virus by the intranasal route on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 7. Mouse body weight (A) and survival (B) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments. Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and LL-37 treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and sLL-37 treated groups. (C) Groups of three mice (Female, 6–8 week old Balb/c) were inoculated with 10 MLD50 of A/PR/8/34 virus intranasally on day 0. Mice were nebulized with 200 µl of saline (control) zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and viral titer in the lungs was assessed by plaque assay. Figure is representative of three independent experiments. Figure shows mean values ± SEM. Statistical analysis was performed using a Student t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05).
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pone-0025333-g001: LL-37 Protects Mice Against Influenza Virus Disease.(A,B) Groups of 5 mice were inoculated with 10 MLD50 of A/Puerto Rico/8/1934 influenza virus by the intranasal route on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 7. Mouse body weight (A) and survival (B) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments. Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and LL-37 treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and sLL-37 treated groups. (C) Groups of three mice (Female, 6–8 week old Balb/c) were inoculated with 10 MLD50 of A/PR/8/34 virus intranasally on day 0. Mice were nebulized with 200 µl of saline (control) zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and viral titer in the lungs was assessed by plaque assay. Figure is representative of three independent experiments. Figure shows mean values ± SEM. Statistical analysis was performed using a Student t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05).

Mentions: To determine if LL-37 displayed antiviral activity in a murine model of lethal influenza virus infection, mice (6–8 week old, female Balb/C) were treated with nebulized LL-37 for 1 day prior to and for 7 days post infection with 10×50% Mouse Lethal Doses (MLD50) A/Puerto Rico/8/1934 (H1N1) virus (PR/8). Nebulized zanamivir and a scrambled LL-37 peptide were used as positive and negative controls respectively. Mouse body weight and survival were monitored for 14 days following infection. Mice infected with PR/8 and treated with nebulized saline or control scrambled peptide all showed severe disease with severe weight loss by day 8 post infection. In contrast, mice that received treatment with either LL-37 or the antiviral drug, zanamivir, showed significantly decreased body weight loss (P≤0.05 and P≤0.01 respectively) at 7 dpi (maximum weight loss observed was ∼20%). Weight loss in LL-37 and zanamivir treated mice ceased around day 9 (Figure 1A).


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)

LL-37 Protects Mice Against Influenza Virus Disease.(A,B) Groups of 5 mice were inoculated with 10 MLD50 of A/Puerto Rico/8/1934 influenza virus by the intranasal route on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 7. Mouse body weight (A) and survival (B) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments. Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and LL-37 treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and sLL-37 treated groups. (C) Groups of three mice (Female, 6–8 week old Balb/c) were inoculated with 10 MLD50 of A/PR/8/34 virus intranasally on day 0. Mice were nebulized with 200 µl of saline (control) zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and viral titer in the lungs was assessed by plaque assay. Figure is representative of three independent experiments. Figure shows mean values ± SEM. Statistical analysis was performed using a Student t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198734&req=5

pone-0025333-g001: LL-37 Protects Mice Against Influenza Virus Disease.(A,B) Groups of 5 mice were inoculated with 10 MLD50 of A/Puerto Rico/8/1934 influenza virus by the intranasal route on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 7. Mouse body weight (A) and survival (B) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments. Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and LL-37 treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and sLL-37 treated groups. (C) Groups of three mice (Female, 6–8 week old Balb/c) were inoculated with 10 MLD50 of A/PR/8/34 virus intranasally on day 0. Mice were nebulized with 200 µl of saline (control) zanamivir (500 µg/ml), LL-37 peptide (500 µg/ml) or scrambled LL-37 control peptide (500 µg/ml) once daily from day -1 to day 2. Mice were euthanized on day 3 and viral titer in the lungs was assessed by plaque assay. Figure is representative of three independent experiments. Figure shows mean values ± SEM. Statistical analysis was performed using a Student t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05).
Mentions: To determine if LL-37 displayed antiviral activity in a murine model of lethal influenza virus infection, mice (6–8 week old, female Balb/C) were treated with nebulized LL-37 for 1 day prior to and for 7 days post infection with 10×50% Mouse Lethal Doses (MLD50) A/Puerto Rico/8/1934 (H1N1) virus (PR/8). Nebulized zanamivir and a scrambled LL-37 peptide were used as positive and negative controls respectively. Mouse body weight and survival were monitored for 14 days following infection. Mice infected with PR/8 and treated with nebulized saline or control scrambled peptide all showed severe disease with severe weight loss by day 8 post infection. In contrast, mice that received treatment with either LL-37 or the antiviral drug, zanamivir, showed significantly decreased body weight loss (P≤0.05 and P≤0.01 respectively) at 7 dpi (maximum weight loss observed was ∼20%). Weight loss in LL-37 and zanamivir treated mice ceased around day 9 (Figure 1A).

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