Extracellular Vesicles: Schistosomal Long-Range Precise Weapon to Manipulate the Immune Response

Abstract

Schistosomiasis (Bilharziasis), a neglected tropical disease that affects more than 240 million people around the world, is caused by infection with the helminth parasite Schistosoma. As part of their secretome, schistosomes release extracellular vesicles (EVs) that modulate the host immune response. The EV-harbored miRNAs upregulate the innate immune response of the M1 pathway and downregulate the differentiation toward the adaptive Th2 immunity. A schistosomal egg-derived miRNA increases the percentage of regulatory T cells. This schistosomal-inducible immunoediting process generates ultimately a parasitic friendly environment that is applied carefully as restrained Th2 response is crucial for the host survival and successful excretion of the eggs. Evidence indicates a selective targeting of schistosomal EVs, however, the underlying mechanisms are unclear yet. The effects of the schistosomes on the host immune system is in accordance with the hygiene hypothesis, attributing the dramatic increase in recent decades in allergy and other diseases associated with imbalanced immune response, to the reduced exposure to infectious agents that co-evolved with humans during evolution. Deciphering the bioactive cargo, function, and selective targeting of the parasite-secreted EVs may facilitate the development of novel tools for diagnostics and delivered therapy to schistosomiasis, as well as to immune-associated disorders.

Schistosome immunomodulators

“…The hallmark of the immune response toward schistosomes is the induction of a Th2 response in both humans and mice [ 2 , 4 , 8 – 11 ] and by the generation of regulatory T cells (Tregs) [ 12 – 15 ], regulatory B cells (Bregs) [ 16 – 18 ], anti-inflammatory, alternatively activated macrophages (AAMs, M2 macrophages) [ 19 – 21 ] as well as elevated IgE and eosinophil production [ 4 , 22 ]. Many of the effects of parasite immunomodulators, as reviewed here, act to drive these immunological outputs.…”

Ezh2 harnesses the intranuclear actin cytoskeleton to remodel chromatin in differentiating Th cells

“…The effector Th1 and Th2 lineages are characterized by the expression of the signature cytokines interferon-γ (IFNγ) and interleukin-4 (IL-4), respectively. IFNγ exerts protective functions during intracellular infections and is involved clinically in cases of autoimmune diseases, whereas IL-4 is effective during parasitic infection but is also implicated in allergic reaction ( Avni and Avni, 2021 ; Avni and Koren, 2018 ; Shamriz et al., 2016 ).…”

Role of Fasciola hepatica Small RNAs in the Interaction With the Mammalian Host

“…Interestingly, we observed more similarities between the profiles we obtained and those reported for S. mansoni than with the other F. hepatica experiment (Figure 4A). If we extend the analysis to all the adult EV miRNAs detected in trematodes (reviewed by Sotillo et al, 2020;Avni and Avni, 2021), we consistently observed that the top 10 abundant miRNAs accounted for more than 80% of the total miRNA population. These highly expressed miRNAs correspond to ancient metazoan miRNA families, including miR-10, let-7, miR-71 and the lophotrochozoan specific families: bantam, miR-2, miR-279 and miR-277, among others (Table S5).…”

“…The secretion of EVs was initially described as a means of eliminating unneeded compounds from the cell (Johnstone et al, 1987) but later works reported the mRNA and miRNA cargo within the EVs of mammalian cells suggesting that they have roles in regulation of gene expression (Valadi et al, 2007;Mitchell et al, 2008). In helminths, miRNAs contained in EVs was first reported in the trematode Dicrocoelium dendrticum, soon followed by reports in the clade V nematode Heligmosomoides polygyrus (Bernal et al, 2014;Buck et al, 2014), and later by similar findings in several other nematode, trematode and cestode species (Fromm et al, 2015;Nowacki et al, 2015;Sotillo et al, 2020;Avni and Avni, 2021;Cucher et al, 2021).…”