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

Abstract

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

Exploring the role of macrophages in determining the pathogenesis of liver fluke infection

“…Remarkably, the HDM secreted by F. hepatica (FhHDM) inhibits the development of M1 macrophages, but despite being classified in the same family of peptides, the HDM secreted by C. sinensis (CsHDM) induces an M1 phenotype (Table 1; Lund et al ., 2016; Alvarado et al ., 2017; Kang et al ., 2020). Analysis of the phylogenetic relationship of the HDM peptide family shows that while CsHDM is on the same branch as FhHDM, it is evolutionarily closer to another branch of HDM peptides, the Sm16 peptides, found exclusively in Schistosoma (Shiels et al ., 2020). Characterization of the Sm16 from S. mansoni showed that it was primarily expressed by cercariae and eggs, and like the CsHDM induces a pro-inflammatory response in macrophages.…”

Schistosome immunomodulators

“…Sm16 is highly expressed in cercariae and in early transformed larvae; the protein is released from cercarial acetabular glands during host penetration and can additionally be detected in the schistosomulum tegument [ 31 , 32 ]. Sm16 is expressed in eggs and sporocysts too, but not in male or female adult worms [ 33 ]. The protein is a lipid bilayer binder that forms an approximately 9-subunit oligomer and attaches to the surface of diverse cell types in a polyanion-independent manner [ 31 , 32 , 34 ].…”

“…The protein is a lipid bilayer binder that forms an approximately 9-subunit oligomer and attaches to the surface of diverse cell types in a polyanion-independent manner [ 31 , 32 , 34 ]. Based on sequence and gene organization considerations, Sm16 has been classified as a member of the helminth defense molecule (HDM) protein family, exclusively found in trematodes [ 33 ].…”

“…Evaluation of the transcriptome of human macrophages treated in vitro with synthetic Sm16 (encompassing amino acids 34–117) reveals that the peptide exerts significant impact on gene expression when administered either alone or in the presence of LPS [ 33 ]. Pathways prominently influenced are those involving transcription factors peroxisome proliferator-activated receptor (PPAR) and liver X receptor/retinoid X receptor (LXR/RXR); these play key roles in macrophage metabolism and are considered central to inflammatory responses [ 33 ].…”

Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes

“…The inhibition of the PI3K/ Akt pathway reversed the protective effects of FhHDM-1 on β-cells, confirming a functional role for this pathway in mediating the positive effect of the peptide. 54 Interrogation of numerous parasite and mammalian genomes has established that the helminth defense molecule peptide family is unique to flatworms, 55,56 suggesting an adaptation for a specific biological function while they reside within their mammalian hosts. Testament to this host-parasite relationship, FhHDM-1 is not cytotoxic to mammalian cells, 57 and it does not induce any adverse activity in a broad range of clinically relevant pharmacology assays (unpublished data).…”