Toxoplasma and malaria parasites can still invade human cells even after their supposed motor system is genetically dismantled—a finding that directly contradicts the textbook model of how these pathogens move. This matters because apicomplexan parasites cause devastating diseases including malaria, toxoplasmosis, and cryptosporidiosis, which together kill hundreds of thousands of people each year. For decades, researchers believed that a linear motor—built from actin, myosin, and surface proteins called micronemes—was essential for gliding motility and host-cell invasion. The grant holder’s own work has shown that knocking out core components of this motor does not block invasion. Parasites missing MyoA, actin, AMA1, or MIC2 still glide and invade, albeit at reduced efficiency. This forces a fundamental re-evaluation: either multiple redundant invasion pathways exist, a backup mechanism kicks in, or the entire motor model is wrong. This is fundamental science with no immediate clinical application. The project will systematically test each possibility using a suite of conditional knockout mutants. If it succeeds, it will rewrite the basic understanding of how these parasites invade cells. That deeper knowledge could eventually open new targets for drugs or vaccines—but only after the most basic question is answered: what actually powers invasion?
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Apicomplexan parasites invade the host cell actively in a process that requires the parasites ability to move by gliding motility. This unique form of motility is thought to be powered by the parasites own actin-myosin-system and transmembrane proteins derived from unique secretory organelles (the micronemes) that act as force transmitter. This linear motor model is widely accepted in the field and alternative gliding and invasion mechanisms are seen with some scepticism. Recently we demonstrat ed that the actin-myosin-system of the parasite can be inactivated, without (as predicted by the current model) blocking host-cell invasion. We generated conditional null mutants for core components of the MyoA-motor complex, actin, the micronemal proteins AMA1 and MIC2. Surprisingly, in no cases is invasion blocked due to the absence of these key components and parasites retain at least a residual gliding activity. These results lead to three possibilities that can explain these findings: 1. Components of the invasion machinery show multiple redundancies. 2. A compensatory invasion mechanism is in place that can substitute for the loss of a functional actin-myosin-system. 3. The current model for gliding motility and invasion needs to be revised Within this proposal I will use a holistic, multidisciplinary approach to address these possibilities to find an answer to the most basic question: What mechanisms are involved in host-cell invasion by apicomplexan parasites. The generated knockout parasites, in addition to novel invasion mutants that will be generated during this project represent an invaluable and unique tool to address this important question.
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