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.
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.
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 PLOS NEGLECTED TROPICAL DISEASES
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.