Similarities and differences among the Opisthorchiidae liver flukes: insights from Opisthorchis felineus

Abstract

The foodborne liver trematode Opisthorchis felineus (Rivolta, 1884) is a member of the triad of phylogenetically related epidemiologically important Opisthorchiidae trematodes, which also includes O. viverrini (Poirier, 1886) and Clonorchis sinensis (Loos, 1907). Despite similarity in the life cycle, Opisthorchiidae liver flukes also have marked differences. Two species (O. viverrini and C. sinensis) are recognized as Group 1A biological carcinogens, whereas O. felineus belongs to Group 3A. In this review, we focus on these questions: Are there actual differences in carcinogenicity among these 3 liver fluke species? Is there an explanation for these differences? We provide a recent update of our knowledge on the liver fluke O. felineus and highlight its differences from O. viverrini and C. sinensis. In particular, we concentrate on differences in the climate of endemic areas, characteristics of the life cycle, the range of intermediate hosts, genomic and transcriptomic features of the pathogens, and clinical symptoms and morbidity of the infections in humans. The discussion of these questions can stimulate new developments in comparative studies on the pathogenicity of liver flukes and should help to identify species-specific features of opisthorchiasis and clonorchiasis pathogenesis.

Keywords: Cholangiocarcinoma; Opisthorchis felineus; foodborne trematodes; liver flukes.

Graphical abstract

Fig. 1.

The infection cycle of Opisthorchis felineus. The life cycle is typical for trematodes with 2 intermediate hosts (freshwater Bithynia spp. snails and Cyprinidae fish) and 1 definitive host (mammals including humans). Created with BioRender.com.

Fig. 2.

Life stages of the liver fluke Opisthorchis felineus and histological consequences for mammalian infection. (A) Metacercariae; (B) hatching eggs with miracidia stained with 4′,6-diamidino-2-phenylindole (DAPI); (C) an adult worm; (D) a liver fluke inside a hamster bile duct (E, epithelium; OF, O. felineus; PF, periductal fibrosis); (E) an infected hamster liver stained with an anti-OF thioredoxin peroxidase (OF_TpX) antibody (BD, bile duct); (F) advanced cholangiofibrosis in an O. felineus-infected hamster at 6 months after infection initiation is recognized to be precancerous; (G) cholangiocarcinoma in an O. felineus-infected hamster after dimethylnitrosamine treatment at 6 months p.i.

Fig. 3.

Proposed mechanisms of carcinogenicity induced by the liver fluke infection. Chronic inflammation leads to the activation of signalling pathways that can induce oncogenes or stimulate epithelial–mesenchymal transition. Fluke-derived substances (extracellular vesicles and proteins) and metabolites secreted into the bile duct may induce oxidative lesions that facilitate DNA damage. In addition, physical damage to host tissues together with the active wound-healing process facilitates recurrent wound healing and cell proliferation. Cofactors such as dietary nitrosamines or changes in the microbiota may promote this pathology. Combined parasite–host interaction events (chronic inflammation, parasite-derived substances and physical damage) alter cell growth, proliferation and survival thereby possibly causing carcinogenesis. Created with BioRender.com.

Fig. 4.

The phylogenetic tree and mRNA abundance of genes encoding CAP domain-containing proteins. (A) The neighbour-joining phylogenetic tree without distance correction. A comparison of O. felineus venom allergen-like proteins with selected members of the CAP superfamily. The sequences were aligned with clustalw2. Pry1 (NP_012456.1, sterol-binding protein of Saccharomyces cerevisiae), SmVAL-4 [XP_018652935.1, venom allergen-like (VAL) 4 protein of Schistosoma mansoni], CsVAL-28 (AWV55762.1, venom allergen-like protein 28 of Clonorchis sinensis), BmVAL-1 (AAK12274.1, venom allergen antigen-like protein 1 of Brugia malayi) and HpVAL-4 (AEP82919.1, venom allergen/ancylostoma secreted protein-like 4 of Heligmosomoides polygyrus bakeri) were used. (B) Interspecies differences in mRNA abundance of genes coding for VAL proteins among adult liver flukes. Normalized data were taken from the paper (Ershov et al., 2019) and were formatted as a heatmap using the heatmap.2 (v.2.38) R package. OF, O. felineus; OV, O. viverrini; CS, C. sinensis. GenBank accession numbers for sequences encoding CAP domain-containing proteins in the Opisthorchiidae liver flukes are presented in Supplementary Table ST1.