Peptides against influenza: evaluating the anti-viral characteristics of regenerating Islet Derived Protein 3 and the cathelicidin LL-37
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Abstract
Antimicrobial peptides (AMPs) are innate host defense peptides that protect against
pathogenic microbes by neutralizing toxins or via a direct killing mechanism. AMPs are
classified based on their physical properties such as charge, structure, and binding motifs.
Here we investigated the antimicrobial and immune-modulating effects of the
Regenerating Islet-Derived Protein 3 (REG3) family and LL-37
REG3 peptides are C-type lectins and have been demonstrated to have antimicrobial
activity against Gram-positive bacteria by binding to sugars on the peptidoglycan
membrane of these bacteria. A similar strategy is also employed by the lectin Surfactant
Protein-D which has been shown to bind and neutralize Influenza A Virus (IAV). REG3
peptides were shown to be expressed in the lungs of mice infected with IAV. We observed
reduction of IAV infected cells when IAV was pre-incubated with an Escherichia coliexpressed
recombinant version of human REG3A peptide. This peptide also modified
interaction of IAV with primary human neutrophils. However, these effects were lost when
using a mammalian cell expressed recombinant REG3A. A second member of the REG3
family, REG3G, showed minimal inhibition of IAV infection.
While the mechanism remains unclear, LL-37 has demonstrated killing activity against a
spectrum of microbes including IAV. Previous work from our group identified the core
domain of LL-37 responsible for IAV neutralization. In addition, our group showed that
LL-37 modulates interaction of IAV with neutrophils. Here we tested three modified
versions of LL-37 that retain the overall size and charge of LL-37, but with modifications
in the core domain reducing hydrophobicity. We observed that these mutants retain IAV
killing activity across multiple strains. In addition, these mutants retain the modulation of
IAV induced neutrophil responses. We also found that the compounds sodium butyrate and
Entinostat, which can upregulate endogenous expression of LL-37, have variable effects in
IAV infection. We believe these findings will aid in the development of LL-37 derivatives
to expand the repertoire of antimicrobials.