Albendazole specifically disrupts microtubules and protein turnover in the tegument of the cestode Mesocestoides corti
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Abstract
Parasitic flatworms, such as cestodes and trematodes, are covered by a syncytial tissue known as the tegument. It consists of a superficial band of cytoplasm (the distal tegument) that is connected by cytoplasmic bridges to multiple cell bodies (cytons) that lay beneath the basal lamina and contain the nuclei. We characterized the cytoskeleton of the tegument of the model cestode Mesocestoides corti and determined the effects of albendazole and albendazole sulfoxide on its organization. These anthelmintics are known to target beta-tubulin in helminths, and their effects have been extensively studied in nematodes, but the specific cells and tissues that are affected are not well understood in parasitic flatworms. Using antibodies that detect different tubulin subunits and post-translational modifications, we show that microtubules in the distal tegument have a unique organization, with bouquets of microtubules radiating from the cytoplasmic bridges, suggesting a role in intracellular traffic. In contrast, actin filaments were largely absent from the distal tegument. The microtubules of the tegument were specifically sensitive to low, chemotherapeutically relevant concentrations of albendazole and albendazole sulfoxide. This was correlated with the accumulation of secretory material in the cytons, and low concentrations of albendazole strongly reduced the incorporation of newly synthesized proteins in the distal tegument, as determined by metabolic labeling. Unexpectedly, albendazole also induced a global decrease in protein synthesis, which was independent of the activation of the unfolded protein response. Our work identifies the tegument as a sensitive target of benzimidazoles in cestodes and indicates that translational inhibition may contribute to the anthelmintic effect of benzimidazoles.
Author Summary
Infections caused by cestodes, such as Echinococcus spp. and Taenia spp., pose a large burden on global human health. These parasites are covered by a very particular epidermis, a syncytial tegument, which is the only contact surface between the parasite and the host. The only chemotherapy available for these infections are benzimidazoles, such as albendazole. From work in other helminths, it is well known that beta-tubulin is the molecular target of benzimidazoles, however, the affected cells and tissues are not known in flatworms. Here, we use the model cestode Mesocestoides corti to address some basic features of the tegument such as the organization of the cytoskeleton, and the effects of therapeutically relevant concentrations of albendazole in this tissue. We found that microtubules are abundant and highly organized in the tegument, and are specifically sensitive to albendazole, in comparison with other cells and tissues. Albendazole reduced the incorporation of new proteins in the tegument and produced an unexpected overall decrease in protein synthesis, which may also be of relevance for chemotherapy. Our results indicate that the tegument is a sensitive cellular target of benzimidazoles.
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Treatment of M. corti larvae with 10 μM colchicine for six hours did not result in any discernible effects on tegumental microtubules, and the microtubules of the distal tegument only disappeared when larvae were treated with 100 μM colchicine (Fig 4A).
Are the microtriches impacted by these drugs?
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Exposure to ABZ or ABZSO resulted in the complete loss of microtubules in the distal tegument (Fig 4A,B), while no effect was observed in solvent controls with dimethyl sulfoxide (DMSO).
In the representative images (Fig 4A), it looks like the drug treatments reduce the length of the distal tegument; however, in 4D, the ABZ treatment seems to have increased the size.
I know y'all mentioned that distal tegument thickness can range from 5-11 µm across the body, but I think it'd be helpful to have some quantification to indicate if the MT structure is necessary for dt structure/size.
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