Role of Toxoplasma mitochondrial respiration and ATP synthesis in parasite survival, virulence, and persistence – a complex story!

Apicomplexan parasites cause severe diseases, including toxoplasmosis and malaria. Toxoplasmosis can be fatal in immunocompromised patients and persists for life. Drug resistance and side effects necessitate new drugs. The apicomplexan mitochondrial electron transport chain (mETC) and ATP synthase pathway offers excellent opportunities to develop better drugs, because this pathway is critical for parasite survival and virulence and has striking differences from the human pathway. We recently found that each of the parasite enzymes consists of different subunits and show structural differences from their human parallels(1–3), manifesting in selective sensitivity to inhibitors, e.g the clinically used atovaquone. Yet, the function of the new subunits and how these differences lead to increased drug sensitivity in the parasite are not understood, hindering the development of better drugs. Moreover, some new subunits are essential for virulence in animals, and mETC inhibitors further kill bradyzoites, the persistent life- stage. Yet the pathway’s role during animal infection and bradyzoites biology remain largely understudied. This work will generate mechanistic understanding of divergent aspects of apicomplexan mETC and ATP synthase, reveal their role during animal infection, and develop studies of their role during persistence. We will further elicit inhibitor mode-of-action, together informing drug development for toxoplasmosis and potentially malaria.