The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins

J Gen Virol. 2013 Jan;94(Pt 1):40-49. doi: 10.1099/vir.0.045013-0. Epub 2012 Oct 10.

Abstract

LL-37, the only human cathelicidin, is a cationic antimicrobial peptide with antibacterial and antifungal activity. LL-37 is released from neutrophil granules and produced by epithelial cells. It has been implicated in host defence against influenza A virus (IAV) in recent studies. We now demonstrate dose-related neutralizing activity of LL-37 against several seasonal and mouse-adapted IAV strains. The ability of LL-37 to inhibit these IAV strains resulted mainly from direct effects on the virus, since pre-incubation of virus with LL-37 was needed for optimal inhibition. LL-37 bound high-density lipoprotein (HDL), and pre-incubation of LL-37 with human serum or HDL reduced its antiviral activity. LL-37 did not inhibit viral association with epithelial cells as assessed by quantitative RT-PCR or confocal microscopy. This finding contrasted with results obtained with surfactant protein D (SP-D). Unlike collectins or human neutrophil defensins (HNPs), LL-37 did not induce viral aggregation under electron microscopy. In the electron microscopy studies, LL-37 appeared to cause disruption of viral membranes. LL-37 had additive antiviral activity when combined with other innate inhibitors like SP-D, surfactant protein A and HNPs. Unlike HNPs, LL-37 did not bind SP-D significantly. These findings indicate that LL-37 contributes to host defence against IAV through a mechanism distinct from that of SP-D and HNPs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / metabolism
  • Antimicrobial Cationic Peptides / immunology
  • Antimicrobial Cationic Peptides / pharmacology*
  • CHO Cells
  • Collectins / immunology
  • Collectins / metabolism
  • Cricetinae
  • Cricetulus
  • Defensins / immunology
  • Defensins / metabolism*
  • Dogs
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Humans
  • Influenza A Virus, H3N2 Subtype / drug effects*
  • Influenza A Virus, H3N2 Subtype / immunology
  • Influenza A Virus, H3N2 Subtype / metabolism*
  • Influenza A virus / immunology
  • Influenza A virus / metabolism*
  • Lipoproteins, HDL / immunology
  • Lipoproteins, HDL / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / virology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Pulmonary Surfactant-Associated Protein A / immunology
  • Pulmonary Surfactant-Associated Protein A / metabolism
  • Pulmonary Surfactant-Associated Protein D / immunology
  • Pulmonary Surfactant-Associated Protein D / metabolism*

Substances

  • Antibodies, Neutralizing
  • Antimicrobial Cationic Peptides
  • Collectins
  • Defensins
  • Lipoproteins, HDL
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Protein D
  • ropocamptide