Immuno-evasive tactics by schistosomes identify an effective allergy preventative

Abstract

Many chronic inflammatory diseases can be improved by helminth infection, but the mechanisms are poorly understood. Allergy and helminthiasis are both associated with Th2-like immune responses; thus, defining how infection with parasites leads to reduced allergy has been particularly challenging. We sought to better understand this conundrum by evaluating host-parasite interactions involved in Th2 immunity in human schistosomiasis. Immune cells were cultured with schistosomes and the effect on CD23, an IgE receptor associated with resistance in schistosomiasis, was evaluated. Cells treated with schistosomes demonstrated reduced surface CD23 levels with a parallel accumulation of soluble (s) CD23 suggesting this IgE receptor is proteolytically cleaved by the parasite. Consistent with this hypothesis, a schistosome-generated (SG)-sCD23 fragment of 15kDa was identified. SG-sCD23 inhibited IgE from binding to CD23 and FcεRI, but lacked the ability to bind CD21. These results suggested that schistosomes target IgE-mediated immunity in immuno-evasive tactics. Based on its characteristics, we predicted that SG-sCD23 would function as an efficacious allergy preventative. Treatment of human FcεRI-transgenic mice with recombinant (r) SG-sCD23 reduced the ability of human IgE to induce an acute allergic response in vivo. In addition, an optimized form of rSG-sCD23 with an introduced point mutation at Asp258 (D258E) to stabilize IgE binding had increased efficacy compared to native rSG-sCD23. Schistosome infection may thus inhibit allergic-like protective immune responses by increasing soluble IgE decoy receptors. Allergy treatments based on this naturally occurring phenomenon may be highly effective and have fewer side effects with long-term use.

Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles

“…CsVAL has also displayed inhibitory activity on IgE-mediated degranulation of mast cells via targeting downstream pathways ( 156 ). Prevention of IgE receptor signaling has also been observed during exposure of human PBMCs to S. mansoni ( 158 ). It was revealed that the worm is able to secrete a component termed as schistosome-generated (SG) sCD23 which not only functions as a soluble decoy for the IgE receptor but also decreases the expression of this receptor ( 158 ).…”

Sm‐p80‐based schistosomiasis vaccine: double‐blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission‐blocking efficacy

“…The Sm‐p80 protein plays an important role in the surface membrane biogenesis and turnover, a process utilized by hemo‐helminths to escape host immune responses . Sm‐p80 is also implicated in additional immune‐evasion tactics utilized by the parasite, including cleavage of the host CD23, as well as degradation of fibronectin to inhibit blood clot formation around the worm in vivo …”

“…22 The Sm-p80 protein plays an important role in the surface membrane biogenesis and turnover, a process utilized by hemo-helminths to escape host immune responses. 22 Sm-p80 is also implicated in additional immune-evasion tactics utilized by the parasite, including cleavage of the host CD23, 23 as well as degradation of fibronectin to inhibit blood clot formation around the worm in vivo. 24 The present study reports the vaccine efficacy of Sm-p80 with a Toll-like receptor 4 agonist-based adjuvant, glucopyranosyl lipid A in an oil-in water emulsion (GLA-SE), 25 in four independent doubleblind experiments with 40 baboons.…”

Development of a schistosomiasis vaccine

“…One of the reasons for this slow progress in developing an effective schistosome vaccine is due to the inherent capability of the parasites to effectively evade their host’s defensive immune responses [33;34]. Nonetheless, in three separate meetings, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) i and the Bill & Melinda Gates Foundation ii , the role of a schistosomiasis vaccine and other tools in context of schistosomiasis control and elimination strategies were discussed.…”