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Sm16 is a 16 KDa protein released by Schistosoma mansoni that modulates inflammatory responses in host cells. Sm16 is expressed by several life cycle stages of S. mansoni, including the egg stage. Schistosome eggs are known to provoke chronic schistosomiasis pathology, which involves the development of liver fibrosis. Hepatic stellate cells (HSCs), which are responsible for this fibrosis, are susceptible to immunomodulation by S. mansoni whole egg secretions. To define the effects of Sm16 exposure on HSCs, two synthetic peptide derivatives of Sm16, coined "KS-84″ and "KS-66″, were tested against LX-2 cells, an immortalised human HSC line, and RNA sequencing was used to assess the transcriptional changes induced by each peptide. In total, 78 and 798 genes were found to be significantly differentially expressed by KS-84 and KS-66 treatment, respectively. In silico pathway analysis of these genes revealed that KS-84 reduced LX-2 cell activation and fibrotic potential, whereas KS-66 increased both processes. Reduced transforming growth factor-β1 (TGF-β1) signalling was identified as a potential mechanism of KS-84-induced inhibition of LX-2 activation. Taken together, these findings indicate a potential role for Sm16 in combatting fibrotic liver disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects.

• S. mansoni eggs secrete at least 266 proteins, 78 more than previously reported. • S. mansoni , S. japonicum and S. haematobium egg secretions vary in complexity. • Shared components between species include vesicle-associated and detox proteins. • Potential pathology causing proteins appear unique to each secretome. • Varied secretions likely influence species-specific pathology and disease severity. Morbidity associated with hepatic and urogenital schistosomiasis stems primarily from the host immune response directed against schistosome eggs. When eggs become entrapped in host tissues, the development of fibrotic plaques drives downstream pathology. These events occur due to the antigenic nature of egg excretory/secretory products (ESPs). Both Schistosoma mansoni and S. japonicum ESPs have been shown to interact with several cell populations in the host liver including hepatocytes, macrophages, and hepatic stellate cells, with both immunomodulatory and pathological consequences. Several protein components of the ESPs of S. mansoni and S. japonicum eggs have been characterised; however, studies into the collective contents of schistosome egg ESPs are lacking. Utilising shotgun mass spectrometry and an array of in silico analyses, we identified 266, 90 and 50 proteins within the S. mansoni, S. japonicum and S. haematobium egg secretomes respectively. We identified numerous proteins with already established immunomodulatory activities, vaccine candidates and vesicle markers. Relatively few common orthologues within the ESPs were identified by BLAST, indicating that the three egg secretomes differ in content significantly. Having a clearer understanding of these components may lead to the identification of new proteins with uncharacterised immunomodulatory potential or pathological relevance. This will enhance our understanding of host-parasite interactions, particularly those occurring during chronic schistosomiasis, and pave the way towards novel therapeutics and vaccines. [ABSTRACT FROM AUTHOR]

Helminth pathogens prepare a Th2 type immunological environment in their hosts to ensure their longevity. They achieve this by secreting molecules that not only actively drive type 2 responses but also suppress type 1 responses. Here, we show that the major cysteine proteases secreted from the helminth pathogens Fasciola hepatica (FheCL1) and Schistosoma mansoni (SmCB1) protect mice from the lethal effects of lipopolysaccharide by preventing the release of inflammatory mediators, nitric oxide, interleukin-6, tumor necrosis factor n, and interleukin12, from macrophages. The proteases specifically block the MyD88-independent TRIF-dependent signaling pathway of Toll-like receptor (TLR)4 and TLR3. Microscopical and flow cytometric studies, however, show that alteration of macrophage function by cysteine protease is not mediated by cleavage of components of the TLR4 complex on the cell surface but occurs by degradation of TLR3 within the endosome. This is the first study to describe a parasite molecule that degrades this receptor and pinpoints a novel mechanism by which helminth parasites modulate the innate immune responses of their hosts to suppress the development of Th1 responses. [ABSTRACT FROM AUTHOR]