PLoS ONE. Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37

[Giuseppe]

[Source: PLoS ONE, full text: (LINK). Abstract, edited.]

Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37


‎by Peter G. Barlow, Pavel Svoboda, Annie Mackellar, Anthony A. Nash, Ian A. York, Jan Pohl, Donald J. Davidson, Ruben O. Donis


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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[Anne]

Re: PLoS ONE. Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37

and cathelicidin depends on vit D level
Back to the future: a new look at ?old? vitamin D

The transcriptional regulation of LL37 by 1,25(OH)₂D has been described in a variety of cell types including macrophages (Liu et al. 2006, 2007b), myeloid cells (Gombart et al. 2005), keratinocytes (Schauber et al. 2007), decidual cells (Evans et al. 2006), and lung epithelial cells (Yim et al. 2007).

Vitamin D signaling and the regulation of macrophage innate immunity. Proposed pathways for the extracellular entry, intracellular movement, mitochondrial metabolism, and nuclear response to vitamin D during macrophage innate immune responses. Serum 25-hydroxyvitamin D (25D) bound to vitamin D-binding protein (DBP) is internalized by macrophages either through passive diffusion of ?free? 25D or via megalin (meg)-mediated uptake. Intracellular 25D is then translocated to mitochondrial 25-hydroxyvitamin D-1α-hydroxylase (CYP27b1) in association with constitutive heat-shock protein 70 (hsc70). The resulting 1,25-dihydroxyvitamin D (1,25D) produced by CYP27b1 is then translocated to the nucleus in conjunction with hsc70 and Bcl-2-associated athanogene (BAG-1). Within the nucleus, 1,25D binds to the vitamin D receptor (VDR), which is then able to form a heterodimer with the retinoid X receptor (RXR). Interaction between the VDR-RXR dimer and vitamin D response elements (VDRE) in the promoters of target genes such as the antimicrobial protein cathelicidin (LL37) is controlled by the VDRE-binding protein (VDRE-BP). Intracrine 1,25D-mediated transcriptional regulation of LL37 in this fashion increases availability of the antimicrobial protein for killing of bacteria in phagosomes fused with lysosomes (phago-lysosomes).


http://joe.endocrinology-journals.org/content/198/2/261.full