Persistence of regenerative stem cells provides a cellular basis for the parasitostatic activity of albendazole against Echinococcus multilocularis
Year: 2026
Type: preprint
Abstract: Albendazole (ABZ) is the mainstay of chemotherapy for alveolar echinococcosis caused by the larval stage of Echinococcus multilocularis , but its activity is predominantly parasitostatic rather than parasiticidal. The cellular basis of this remarkable parasite persistence remains poorly understood. Here, we investigated the effects of sustained ABZ exposure on the germinative stem cells that drive metacestode growth and regeneration and examined whether differential β-tubulin isoform usage could contribute to their drug susceptibility. ABZ rapidly impaired microtubule-dependent tegumental transport and caused pronounced damage to metacestode vesicles. In contrast, proliferative germinative cells (GC) persisted during prolonged and continuous ABZ exposure. Importantly, cells surviving 14–28 days of treatment retained developmental competence, regenerated metacestode vesicles following drug withdrawal, and, after extended exposure to 10 µM ABZ, remained capable of generating parasite tissue following transplantation into a permissive host. Transcriptomic and immunohistochemical analyses identified the Y200-containing β-tubulin isoform Tub-2 as a major metacestode β-tubulin that is almost exclusively associated with the proliferative GC lineage. Tub-2 was present in virtually all S-phase cells, colocalized with established GC markers, localized to mitotic spindles, and Tub-2+ cells persisted during prolonged ABZ and ABZ-SO exposure. Structural analysis further revealed an E198–Y200 interaction in Tub-2, providing a structural correlate of the resistance-associated Y200 configuration. Together, these findings provide a cellular explanation for the predominantly parasitostatic activity of benzimidazoles against E. multilocularis . ABZ profoundly damages parasite tissue while sparing a regenerative cell compartment capable of re-establishing metacestode growth after drug withdrawal. They further identify GC-associated Tub-2 as a plausible molecular contributor to this persistence and as a potential target for curative anti- Echinococcus chemotherapy. Author Summary Alveolar echinococcosis is a severe parasitic disease caused by the larval stage of E. multilocularis . Treatment relies mainly on albendazole (ABZ), which can control parasite growth but usually does not eliminate the infection, making long-term or even lifelong therapy necessary. The biological reasons for this remarkable persistence are poorly understood. Here, we show that ABZ severely damages parasite tissue while a population of proliferating germinative stem cells survives even prolonged drug exposure. Importantly, these cells retain the ability to regenerate parasite tissue after ABZ is removed. We further identify the β-tubulin isoform Tub-2 as being strongly associated with these germinative cells and show structural features that may contribute to reduced ABZ susceptibility. Our findings suggest that the failure of ABZ to eliminate the parasite may result from its inability to eradicate the regenerative stem cell compartment. Drugs that specifically eliminate these cells could therefore provide a route towards curative treatment of alveolar echinococcosis.
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213451848