Abstract
BackgroundThe liver fluke Opisthorchis viverrini infects several million people in Southeast Asia. Adult flukes live in the bile ducts of humans, where they cause hepatobiliary pathology, including cholangiocarcinoma. Here, we investigated the potential of extracellular vesicles (EVs) secreted by the fluke and defined recombinant proteins derived from EVs to generate protective immunity in a hamster vaccination-challenge model.Methodology/Principal findingsEVs isolated from the excretory-secretory products of O. viverrini and two recombinant EV surface proteins encoding the large extracellular loops (LEL) of Ov-TSP-2 (rOv-TSP-2) and Ov-TSP-3 (rOv-TSP-3) were adjuvanted and used to vaccinate hamsters intraperitoneally followed by challenge infection with O. viverrini metacercariae. The number of adult flukes recovered from hamsters immunized with EVs, rOv-TSP-2, rOv-TSP-3 and rOv-TSP-2+rOv-TSP-3 were significantly reduced compared to control animals vaccinated with adjuvant alone. The number of eggs per gram feces was also significantly reduced in hamsters vaccinated with rOv-TSP-2 compared to controls, but no significant differences were found in the other groups. The average length of worms recovered from hamsters vaccinated with EVs, rOv-TSP-2 and rOv-TSP-3 was significantly shorter than that of worms recovered from the control group. Anti-EV IgG levels in serum and bile were significantly higher in hamsters vaccinated with EVs compared to control hamsters both pre- and post-challenge. In addition, levels of anti-rOv-TSP antibodies in the serum and bile were significantly higher than control hamsters both pre- and post-challenge. Finally, antibodies against rOv-TSP-2 and rOv-TSP-3 blocked uptake of EVs by human primary cholangiocyte in vitro, providing a plausible mechanism by which these vaccines exert partial efficacy and reduce the intensity of O. viverrini infection.Conclusion/SignificanceLiver fluke EVs and recombinant tetraspanins derived from the EV surface when administered to hamsters induce antibody responses that block EV uptake by target bile duct cells and exert partial efficacy and against O. viverrini challenge.
Highlights
The human liver fluke Opisthorchis viverrini is endemic in different countries of Southeast Asia including Thailand, Lao PDR, Cambodia, southern part of Vietnam and Myanmar [1, 2]
This is the first report of successful vaccination of hamsters with O. viverrini extracellular vesicles (EVs) and recombinant vesicle surface proteins, and provides proof-of-concept for development of subunit vaccines for this carcinogenic infection
Vaccination of hamster with extracellular vesicles and tetraspanins from liver fluke in 91% ( P
Summary
The human liver fluke Opisthorchis viverrini is endemic in different countries of Southeast Asia including Thailand, Lao PDR, Cambodia, southern part of Vietnam and Myanmar [1, 2]. Liver fluke infection is associated with a high incidence of liver pathology including cholangiocarcinoma (CCA) [3, 4]. O. viverrini-induced hepatobiliary damage is multi-factorial, and includes several factors such as mechanical damage of the epithelium by the suckers of the worm, secreted parasite metabolites [7, 8] and different immunopathological processes [9]. The liver fluke Opisthorchis viverrini infects several million people in Southeast Asia. Adult flukes live in the bile ducts of humans, where they cause hepatobiliary pathology, including cholangiocarcinoma. We investigated the potential of extracellular vesicles (EVs) secreted by the fluke and defined recombinant proteins derived from EVs to generate protective immunity in a hamster vaccination-challenge model
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