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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 antiviral activity against influenza virus in vitro.Influenza virus was pre-incubated with cathelicidin peptide or control peptide scrambled LL-37 (sLL-37) (A) at a range of concentrations as indicated for 1 hour at room temperature and a plaque formation assay was then performed to assess virus titer in MDCK-L cells in the presence of trypsin. Viruses used were A/PR/8/34 (H1N1) (A, B) or A/Udorn/307/72 (C). The antiviral activity of the cathelicidins LL-37 (A, C), mCRAMP (B) and Protegrin-1 (B) was assessed. Figures are representative of at least three independent experiments. Figures show mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus only titer with virus + peptide (*P≤0.05, ** P≤0.01).
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pone-0025333-g004: Cathelicidins show antiviral activity against influenza virus in vitro.Influenza virus was pre-incubated with cathelicidin peptide or control peptide scrambled LL-37 (sLL-37) (A) at a range of concentrations as indicated for 1 hour at room temperature and a plaque formation assay was then performed to assess virus titer in MDCK-L cells in the presence of trypsin. Viruses used were A/PR/8/34 (H1N1) (A, B) or A/Udorn/307/72 (C). The antiviral activity of the cathelicidins LL-37 (A, C), mCRAMP (B) and Protegrin-1 (B) was assessed. Figures are representative of at least three independent experiments. Figures show mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus only titer with virus + peptide (*P≤0.05, ** P≤0.01).

Mentions: To assess the direct antiviral activity of cathelicidins in vitro, we incubated PR/8 with varying concentrations of cathelicidin peptides or control scrambled peptide, for 1 hour at room temperature and measured virus titer by plaque assay. Exposure to physiologically relevant concentrations of LL-37 led to approximately 90% reductions in virus titer (p≤0.05) (Figure 4A). Control scrambled LL-37 had no effect on the virus titer. The murine mCRAMP peptide also displayed anti-influenza virus activity and induced a significant decrease in virus titer following exposure (P≤0.05; Figure 4B). However, consistent with the in vivo observations, the porcine cathelicidin Protegrin-1 did not demonstrate any anti-influenza activity in this assay (Figure 4B).


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 antiviral activity against influenza virus in vitro.Influenza virus was pre-incubated with cathelicidin peptide or control peptide scrambled LL-37 (sLL-37) (A) at a range of concentrations as indicated for 1 hour at room temperature and a plaque formation assay was then performed to assess virus titer in MDCK-L cells in the presence of trypsin. Viruses used were A/PR/8/34 (H1N1) (A, B) or A/Udorn/307/72 (C). The antiviral activity of the cathelicidins LL-37 (A, C), mCRAMP (B) and Protegrin-1 (B) was assessed. Figures are representative of at least three independent experiments. Figures show mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus only titer with virus + peptide (*P≤0.05, ** P≤0.01).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025333-g004: Cathelicidins show antiviral activity against influenza virus in vitro.Influenza virus was pre-incubated with cathelicidin peptide or control peptide scrambled LL-37 (sLL-37) (A) at a range of concentrations as indicated for 1 hour at room temperature and a plaque formation assay was then performed to assess virus titer in MDCK-L cells in the presence of trypsin. Viruses used were A/PR/8/34 (H1N1) (A, B) or A/Udorn/307/72 (C). The antiviral activity of the cathelicidins LL-37 (A, C), mCRAMP (B) and Protegrin-1 (B) was assessed. Figures are representative of at least three independent experiments. Figures show mean values ± SEM. Statistical analysis was performed using an unpaired t-test to compare virus only titer with virus + peptide (*P≤0.05, ** P≤0.01).
Mentions: To assess the direct antiviral activity of cathelicidins in vitro, we incubated PR/8 with varying concentrations of cathelicidin peptides or control scrambled peptide, for 1 hour at room temperature and measured virus titer by plaque assay. Exposure to physiologically relevant concentrations of LL-37 led to approximately 90% reductions in virus titer (p≤0.05) (Figure 4A). Control scrambled LL-37 had no effect on the virus titer. The murine mCRAMP peptide also displayed anti-influenza virus activity and induced a significant decrease in virus titer following exposure (P≤0.05; Figure 4B). However, consistent with the in vivo observations, the porcine cathelicidin Protegrin-1 did not demonstrate any anti-influenza activity in this assay (Figure 4B).

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