Comparative Proteomic Analysis of Triclabendazole Response in the Liver Fluke Fasciola hepatica

Abstract

Control of Fasciola hepatica infections of livestock in the absence of vaccines depends largely on the chemical triclabendazole (TCBZ) because it is effective against immature and adult parasites. Overdependence on a single drug and improper application is considered a significant factor in increasing global reports of fluke resistant to TCBZ. The mode(s) of action and biological target(s) of TCBZ are not confirmed, delaying detection and the monitoring of early TCBZ resistance. In this study, to further understand liver fluke response to TCBZ, the soluble proteomes of TCBZ-resistant and TCBZ-susceptible isolates of F. hepatica were compared with and without in vitro exposure to the metabolically active form of the parent drug triclabendazole sulphoxide (TCBZ-SO), via two-dimensional gel electrophoresis (2-DE). Gel image analysis revealed proteins displaying altered synthesis patterns and responses both between isolates and under TCBZ-SO exposure. These proteins were identified by mass spectrometry supported by a F. hepatica expressed sequence tag (EST) data set. The TCBZ responding proteins were grouped into three categories; structural proteins, energy metabolism proteins, and "stress" response proteins. This single proteomic investigation supported the reductionist experiments from many laboratories that collectively suggest TCBZ has a range of effects on liver fluke metabolism. Proteomics highlighted differences in the innate proteome profile of different fluke isolates that may influence future therapy and diagnostics design. Two of the TCBZ responding proteins, a glutathione transferase and a fatty acid binding protein, were cloned, produced as recombinants, and both found to bind TCBZ-SO at physiologically relevant concentrations, which may indicate a role in TCBZ metabolism and resistance.

Recombinant Fasciola hepatica fatty acid binding protein suppresses toll-like receptor stimulation in response to multiple bacterial ligands

“…Therefore, they use carriers to uptake such lipids directly from the host and transport them to specific destinations within parasite, a process in which FABP could play an important role. Thus, a major reason for interest in trematode FABPs relies in their potential role in drug delivery 3 and the fact that Fasciola hepatica and Schistosoma mansoni FABPs may be cross-protective antigens 4–7 .…”

Molecular basis underlying the biological effects elicited by extremely low-frequency magnetic field (ELF-MF) on neuroblastoma cells

“…Nowadays, proteomic approach is widely used as a powerful research tool able to detect and characterize any change in protein expression during or following exposure to drugs, stress conditions, etc. [Chemale et al, 2010;Thompson et al, 2010].…”

The helminth parasite proteome at the host–parasite interface – Informing diagnosis and control

“…These are used for treating STH infections and sometimes to target filarial parasites. Although there are treatments for helminth infections, it has been suggested that drug resistant and less susceptible strains for praziquantel have been found in schistosomes (William et al, 2001;Melman et al, 2009;Ismail et al, 1994;Fallon and Doenhoff, 1994) and some strains of F. hepatica and Fasciola gigantica have been found to be resistant against the drug triclabendazole (Chemale et al, 2010). In this study, parasites resistant to triclabendazole showed a decrease in metabolic enzymes, while susceptible parasites showed an increase suggesting that the resistant parasites use an alternative route to produce energy.…”

“…On the contrary Duan et al (2014) recently found that SEA from S. japonicum can reverse hepatic fibrosis through the induction of apoptosis of HSC by SEA. Proteomic studies not only give insight into the pathology, but have the potential to identify intervention targets, which is necessary because strains resistant to anthelmintic drugs have been described (William et al, 2001;Melman et al, 2009;Ismail et al, 1994;Fallon and Doenhoff, 1994;Chemale et al, 2010). Paeniflorin, a herb, relieves liver granuloma and fibrosis in schistosomiasis by the inhibition of HSC proliferation and collagen type I and III secretion (Chu et al, 2007).…”