Eimeria bovis macromeront formation: host cell revitalization by bystander cell-based TNT-mediated mitochondria donation

• Applicant: Professorin Dr. Anja Taubert
• Subject Area: Veterinary Medical Science ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542529445

Eimeria bovis is a global, obligate intracellular parasite, which induces enteric infections in calves thereby significantly affecting both individual animal health and profitability of cattle industry. In the host, large intracellular macromeronts (up to 400 µm) with up to 140,000 merozoites I are formed within approximately three weeks in endothelial host cells. Considering this long-lasting and enormous intracellular proliferation, it seems highly challenging if not impossible for a single host cell to fully satisfy the parasite’s metabolic and energetic needs. We generated convincing evidence that E. bovis-infected endothelial host cells indeed highly suffer from a critical parasite-driven metabolic and energetic exploitation leading to host cell exhaustion and stress-induced premature senescence during macromeront formation. Cell stress is well documented to induce the formation of tunneling nanotubes (TNTs), i. e. thin and long membrane protrusions, which allow molecule and organelle exchange with bystander cells. Hence, senescent endothelial cells were already demonstrated to be rescued via TNT-based mitochondria donation by bystander cells. Of note, we recently documented that non-infected bystander cells accumulate around E. bovis macromeront-carrying host cells (MCHCs). Consequently, we here hypothesize that bystander cell accumulation is linked to the infected host cell’s multi-molecular and -energetic demands, which likewise are compensated by healthy bystander or other repair-competent cell types like endothelial progenitor cells. Therefore, we here intend to study whether endothelial E. bovis infection drives TNT formation and if artificial blockage or stimulation of TNT biogenesis affects merozoite I production. Given that we already demonstrated mitochondrial dysregulation in MCHCs, we will furthermore analyze if bystander cells donate mitochondria or lysosomes (required for the degradation of dysfunctional mitochondria) to infected cells or accept damaged ones for transmitophagy thereby aiding host cells to recover to a normal operating state needed for successful merozoite I generation. Moreover, we will study expression profiles of selected molecules involved in TNT-based mitochondria transfer and analyze whether the secretome of E. bovis-infected host cells influences any of these mechanisms thereby also addressing the role of extracellular vesicles. Given that circulating endothelial progenitor cells own outstanding capacities for TNT-based mitochondria donation, we will furthermore study whether this cell type is attracted by MCHCs and promotes infected host cell revitalization.

• DFG Programme: Research Grants