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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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Cathelicidins Show Species-Specific Antiviral Effects.(A,B,D,E) 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), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) (A and B) or the porcine cathelicidin Protegrin-1 (500 µg/ml) (D and E) once daily from day -1 to day 7. Mouse body weight (A, D) and survival (B, E) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments (A and B) or one experiment (D and E). Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and mCRAMP treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and Protegrin treated groups. (C, F) Groups of three mice were infected with 10 MLD50 of A/PR/8/34 virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) or the porcine cathelicidin Protegrin-1 (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 shows mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05, **P≤0.01, ***P≤0.001).
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pone-0025333-g002: Cathelicidins Show Species-Specific Antiviral Effects.(A,B,D,E) 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), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) (A and B) or the porcine cathelicidin Protegrin-1 (500 µg/ml) (D and E) once daily from day -1 to day 7. Mouse body weight (A, D) and survival (B, E) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments (A and B) or one experiment (D and E). Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and mCRAMP treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and Protegrin treated groups. (C, F) Groups of three mice were infected with 10 MLD50 of A/PR/8/34 virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) or the porcine cathelicidin Protegrin-1 (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 shows mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05, **P≤0.01, ***P≤0.001).

Mentions: LL-37 is a human cathelicidin, although it has previously been shown to have antimicrobial effects in mouse models of infection [27]. To determine if other peptides of the cathelicidin family also conferred protection against influenza virus in vivo, mice were treated with the murine mCRAMP peptide or the porcine Protegrin-1 peptide for 1 day prior to and for 7 days post infection with 10 MLD50 A/PR/8/34 (H1N1) virus. Nebulized zanamivir was used as a positive control. As with LL-37, mice infected with PR/8 and nebulized with mCRAMP lost less weight when compared to control mice that had received only nebulized saline (Figure 2A). Treatment with mCRAMP also dramatically resulted in significantly enhanced survival (Figure 2B, p<0.001) and reduced lung virus titers by approximately 70–80% (Figure 2C). Animals treated with mCRAMP showed similar weight loss, survival, and lung virus titers as those treated with zanamivir (Figure 2A–C). In contrast, mice that had received treatments with nebulized Protegrin-1 peptide lost weight to the same extent as the control-treated animals (Figure 2D), and did not show any statistically significant increase in survival (Figure 2E), or reduction in lung virus titers (Figure 2F).


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 Show Species-Specific Antiviral Effects.(A,B,D,E) 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), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) (A and B) or the porcine cathelicidin Protegrin-1 (500 µg/ml) (D and E) once daily from day -1 to day 7. Mouse body weight (A, D) and survival (B, E) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments (A and B) or one experiment (D and E). Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and mCRAMP treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and Protegrin treated groups. (C, F) Groups of three mice were infected with 10 MLD50 of A/PR/8/34 virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) or the porcine cathelicidin Protegrin-1 (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 shows mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05, **P≤0.01, ***P≤0.001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198734&req=5

pone-0025333-g002: Cathelicidins Show Species-Specific Antiviral Effects.(A,B,D,E) 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), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) (A and B) or the porcine cathelicidin Protegrin-1 (500 µg/ml) (D and E) once daily from day -1 to day 7. Mouse body weight (A, D) and survival (B, E) was monitored daily up to 14 days post infection. Data represent mean values ± SEM, for three independent experiments (A and B) or one experiment (D and E). Statistical analysis was performed using Kaplan Meier with a Mantel-Cox (log rank) test. Survival curves obtained with Zanamivir and mCRAMP treatments were significantly different (P≤0.001) compared to saline control treatment. There was no difference between saline treated and Protegrin treated groups. (C, F) Groups of three mice were infected with 10 MLD50 of A/PR/8/34 virus via intranasal administration on day 0. Mice were nebulized with 200 µl of saline (control), zanamivir (500 µg/ml), the murine cathelicidin mCRAMP (500 µg/ml) or the porcine cathelicidin Protegrin-1 (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 shows mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus infected animals with virus/peptide and virus/zanamivir treated animals (*P≤0.05, **P≤0.01, ***P≤0.001).
Mentions: LL-37 is a human cathelicidin, although it has previously been shown to have antimicrobial effects in mouse models of infection [27]. To determine if other peptides of the cathelicidin family also conferred protection against influenza virus in vivo, mice were treated with the murine mCRAMP peptide or the porcine Protegrin-1 peptide for 1 day prior to and for 7 days post infection with 10 MLD50 A/PR/8/34 (H1N1) virus. Nebulized zanamivir was used as a positive control. As with LL-37, mice infected with PR/8 and nebulized with mCRAMP lost less weight when compared to control mice that had received only nebulized saline (Figure 2A). Treatment with mCRAMP also dramatically resulted in significantly enhanced survival (Figure 2B, p<0.001) and reduced lung virus titers by approximately 70–80% (Figure 2C). Animals treated with mCRAMP showed similar weight loss, survival, and lung virus titers as those treated with zanamivir (Figure 2A–C). In contrast, mice that had received treatments with nebulized Protegrin-1 peptide lost weight to the same extent as the control-treated animals (Figure 2D), and did not show any statistically significant increase in survival (Figure 2E), or reduction in lung virus titers (Figure 2F).

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