No 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.

The human cathelicidin LL-37 is a cationic host defense peptide (antimicrobial peptide) expressed primarily by neutrophils and epithelial cells. This peptide, up-regulated under conditions of inflammation, has immunomodulatory and antimicrobial functions. We demonstrate that LL-37 is a potent inhibitor of human neutrophil apoptosis, signaling through P2X 7 receptors and G-proteincoupled receptors other than the formyl peptide receptor-like-1 molecule. This process involved modulation of Mcl-1 expression, inhibition of BID and procaspase-3 cleavage, and the activation of phosphatidylinositol-3 kinase but not the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. In contrast to the inhibition of neutrophil apoptosis, LL-37 induced apoptosis in primary airway epithelial cells, demonstrating alternate consequences of LL-37-mediated modulation of apoptotic pathways in different human primary cells. We propose that these novel immunomodulatory properties of LL-37 contribute to peptide-mediated enhancement of innate host defenses against acute infection and are of considerable significance in the development of such peptides and their synthetic analogs as potential therapeutics for use against multiple antibioticresistant infectious diseases.

Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.

HighlightsThe host defence peptide LL-37 can reduce Human Rhinovirus 1B (HRV1B) replication in airway epithelial cells.The antiviral activity of LL-37 is sequence specific.LL-37 reduces the metabolic activity of cells infected with HRV1B without inducing substantial apoptotic or necrotic cell death.The antiviral activity of cathelicidin peptides towards HRV1B is conserved in peptides from other mammalian species including pig and sheep.

The global burden of morbidity and mortality arising from viral infections is high; however, the development of effective therapeutics has been slow. As our understanding of innate immunity has expanded over recent years, knowledge of natural host defenses against viral infections has started to offer potential for novel therapeutic strategies. An area of current research interest is in understanding the roles played by naturally occurring cationic host defense peptides, such as the cathelicidins, in these innate antiviral host defenses across different species. This research also has the potential to inform the design of novel synthetic antiviral peptide analogs and/or provide rationale for therapies aimed at boosting the natural production of these peptides. In this review, we will discuss our knowledge of the antiviral activities of cathelicidins, an important family of cationic host defense peptides, and consider the implications for novel antiviral therapeutic approaches.

No abstract

Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.