Gene Expression Profile of Selected Fasciola hepatica Gene Families Implicated in Triclabendazole Resistance
Description
Fasciolosis is caused by liver flukes: F. hepatica, and a sister species – F. gigantica. A growing concern with controlling the disease is resistance to triclabendazole (TCBZ), the only drug shown to kill both adult and immature liver flukes. Currently, F. hepatica mechanism of resistance to TCBZ is not clearly understood and there is no effective commercially available vaccine. Previous work proposed three mechanisms associated with TCBZ mode of action and resistance: tubulin binding activity, drug uptake mechanisms, and drug metabolism mechanism. Exploring evolutionary forces acting on F. hepatica genes associated with TCBZ mode of action and resistance could explain how the parasite develops resistance to the drug, enable identification of potential drug targets, and facilitate development of new drugs. The expression profile of the genes associated with TCBZ mode of action was assessed across F. hepatica life stages. Findings indicate that tubulin gene expression was elevated in metacercariae and newly excysted juveniles (NEJs), with a peak expression pattern noticed in NEJs 1 hour post excystment, with levels reducing in flukes 21 days post excystment. Similarly, in genes associated with TCBZ uptake, expression was predominantly raised in metacercariae and NEJs, while gene expression gradually reduced towards fluke maturity. The effect of TCBZ on F. hepatica was investigated in experimentally infected sheep. Parasite response to the drug in TCBZ resistant and susceptible F. hepatica isolates was compared in sheep infected and treated with the drug. TCBZ treatment induced gene expression patterns were noticed in 72% (90 out 125 genes, P < 0.05) of all the genes assessed (excluding unexpressed genes and constitutively expressed genes). Findings in this study indicate TCBZ administration affects multiple mechanisms in the parasite. Therefore, this confirms that all the three proposed TCBZ mode of action and resistance mechanisms in F. hepatica could be implicated in drug TCBZ resistance.
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Institutions
- University of Liverpool