Silencing of Opisthorchis viverrini Tetraspanin Gene Expression Results in Reduced Secretion of Extracellular Vesicles

Chaiyadet, Sujittra, Sotillo, Javier, Krueajampa, Watchara, Thongsen, Sophita, Smout, Michael, Brindley, Paul J., Laha, Thewarach, and Loukas, Alex (2022) Silencing of Opisthorchis viverrini Tetraspanin Gene Expression Results in Reduced Secretion of Extracellular Vesicles. Frontiers in Cellular and Infection Microbiology, 12. 827521.

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Inter-phylum transfer of molecular information is exquisitely exemplified in the uptake of parasite extracellular vesicles (EVs) by their target mammalian host tissues. The oriental liver fluke, Opisthorchis viverrini is the major cause of bile duct cancer in people in Southeast Asia. A major mechanism by which O. viverrini promotes cancer is through the secretion of excretory/secretory products which contain extracellular vesicles (OvEVs). OvEVs contain microRNAs that are predicted to impact various mammalian cell proliferation pathways, and are internalized by cholangiocytes that line the bile ducts. Upon uptake, OvEVs drive relentless proliferation of cholangiocytes and promote a tumorigenic environment, but the underlying mechanisms of this process are unknown. Moreover, purification and characterization methods for helminth EVs in general are ill defined. We therefore compared different purification methods for OvEVs and characterized the sub-vesicular compartment proteomes. Two CD63-like tetraspanins (Ov-TSP-2 and TSP-3) are abundant on the surface of OvEVs, and could serve as biomarkers for these parasite vesicles. Anti-TSP-2 and -TSP-3 IgG, as well as different endocytosis pathway inhibitors significantly reduced OvEV uptake and subsequent proliferation of cholangiocytes in vitro. Silencing of Ov-tsp-2 and tsp-3 gene expression in adult flukes using RNA interference resulted in substantial reductions in OvEV secretion, and those vesicles that were secreted were deficient in their respective TSP proteins. Our findings shed light on the importance of tetraspanins in fluke EV biogenesis and/or stability, and provide a conceivable mechanism for the efficacy of anti-tetraspanin subunit vaccines against a range of parasitic helminth infections.

Item ID: 73074
Item Type: Article (Research - C1)
ISSN: 2235-2988
Keywords: Opisthorchis viverrini, liver fluke, extracellular vesicle, endocytosis, tetraspanin
Copyright Information: © 2022 Chaiyadet, Sotillo, Krueajampa, Thongsen, Smout, Brindley, Laha and Loukas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC 1117504, NHMRC 1132975
Date Deposited: 16 Mar 2022 08:01
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320211 Infectious diseases @ 40%
31 BIOLOGICAL SCIENCES > 3104 Evolutionary biology > 310407 Host-parasite interactions @ 40%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321101 Cancer cell biology @ 20%
SEO Codes: 20 HEALTH > 2099 Other health > 209999 Other health not elsewhere classified @ 20%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 70%
20 HEALTH > 2001 Clinical health > 200199 Clinical health not elsewhere classified @ 10%
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