Fasciola hepatica-Derived Molecules as Regulators of the Host Immune Response.

Helminths (worms) are one of the most successful organisms in nature given their ability to infect millions of humans and animals worldwide. Their success can be attributed to their ability to modulate the host immune response for their own benefit by releasing excretory-secretory (ES) products. Accordingly, ES products have been lauded as a potential source of immunomodulators/biotherapeutics for an array of inflammatory diseases. However, there is a significant lack of knowledge regarding the specific interactions between these products and cells of the immune response. Many different compounds have been identified within the helminth "secretome," including antioxidants, proteases, mucin-like peptides, as well as helminth defense molecules (HDMs), each with unique influences on the host inflammatory response. HDMs are a conserved group of proteins initially discovered in the secretome of the liver fluke, Fasciola hepatica. HDMs interact with cell membranes without cytotoxic effects and do not exert antimicrobial activity, suggesting that these peptides evolved specifically for immunomodulatory purposes. A peptide generated from the HDM sequence, termed FhHDM-1, has shown extensive anti-inflammatory abilities in clinically relevant models of diseases such as diabetes, multiple sclerosis, asthma, and acute lung injury, offering hope for the development of a new class of therapeutics. In this review, the current knowledge of host immunomodulation by a range of F. hepatica ES products, particularly FhHDM-1, will be discussed. Immune regulators, including HDMs, have been identified from other helminths and will also be outlined to broaden our understanding of the variety of effects these potent molecules exert on immune cells.

Schistosoma mansoni immunomodulatory molecule Sm16/SPO-1/SmSLP is a member of the trematode-specific helminth defence molecules (HDMs).

BACKGROUND: Sm16, also known as SPO-1 and SmSLP, is a low molecular weight protein (~16kDa) secreted by the digenean trematode parasite Schistosoma mansoni, one of the main causative agents of human schistosomiasis. The molecule is secreted from the acetabular gland of the cercariae during skin invasion and is believed to perform an immune-suppressive function to protect the invading parasite from innate immune cell attack. METHODOLOGY/PRINCIPAL FINDINGS: We show that Sm16 homologues of the Schistosomatoidea family are phylogenetically related to the helminth defence molecule (HDM) family of immunomodulatory peptides first described in Fasciola hepatica. Interrogation of 69 helminths genomes demonstrates that HDMs are exclusive to trematode species. Structural analyses of Sm16 shows that it consists predominantly of an amphipathic alpha-helix, much like other HDMs. In S. mansoni, Sm16 is highly expressed in the cercariae and eggs but not in adult worms, suggesting that the molecule is of importance not only during skin invasion but also in the pro-inflammatory response to eggs in the liver tissues. Recombinant Sm16 and a synthetic form, Sm16 (34-117), bind to macrophages and are internalised into the endosomal/lysosomal system. Sm16 (34-117) elicited a weak pro-inflammatory response in macrophages in vitro but also suppressed the production of bacterial lipopolysaccharide (LPS)-induced inflammatory cytokines. Evaluation of the transcriptome of human macrophages treated with a synthetic Sm16 (34-117) demonstrates that the peptide exerts significant immunomodulatory effects alone, as well as in the presence of LPS. Pathways most significantly influenced by Sm16 (34-117) were those involving transcription factors peroxisome proliferator-activated receptor (PPAR) and liver X receptors/retinoid X receptor (LXR/RXR) which are intricately involved in regulating the cellular metabolism of macrophages (fatty acid, cholesterol and glucose homeostasis) and are central to inflammatory responses. CONCLUSIONS/SIGNIFICANCE: These results offer new insights into the structure and function of a well-known immunomodulatory molecule, Sm16, and places it within a wider family of trematode-specific small molecule HDM immune-modulators with immuno-biotherapeutic possibilities.

Sea snake cathelicidin (Hc-cath) exerts a protective effect in mouse models of lung inflammation and infection.

We investigated the anti-inflammatory and antibacterial activities of Hc-cath, a cathelicidin peptide derived from the venom of the sea snake, Hydrophis cyanocyntus, using in vivo models of inflammation and infection. Hc-cath function was evaluated in in vitro, in vivo in the wax moth, Galleria mellonella, and in mouse models of intraperitoneal and respiratory Pseudomonas aeruginosa infection. Hc-Cath downregulated LPS-induced pro-inflammatory responses in macrophages and significantly improved the survival of P. aeruginosa infected G. mellonella over a 5-day period. We also demonstrated, for the first time, that Hc-cath can modulate inflammation in a mouse model of LPS-induced lung inflammation by significantly reducing the release of the pro-inflammatory cytokine and neutrophil chemoattractant, KC, resulting in reduced cellular infiltration into the lungs. Moreover, Hc-cath treatment significantly reduced the bacterial load and inflammation in mouse models of P. aeruginosa intraperitoneal and respiratory infection. The effect of Hc-cath in our studies highlights the potential to develop this peptide as a candidate for therapeutic development.