Investigating mechanisms of chromosome segregation during the exit of male Plasmodium gametes.

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Plasmodium parasites, the causative agents of malaria, have a complex, mostly intracellular life cycle that alternates between a vertebrate and a mosquito host. To move from one stage to the next, these parasites have developed different strategies to leave their host cell. One of the most complex and rapid strategies occurs during early mosquito infection when sexual gametocytes leave their host cell and form gametes. During male gametogenesis, host cell lysis occurs in parallel with the rapid formation of eight flagellated male gametes from a single gametocyte in a highly ordered but poorly understood process. Within a short period of time, the activated male gametocyte replicates its DNA three times without the nucleus dividing. Only when the eight flagella become mobile and the gametes leave the residual body, do they pull a nucleus including the chromosome set with them. As part of the SPP-2225 Exit, we want to elucidate the molecular mechanisms by which the male gametes ensure that they take a complete set of chromosomes with them when they exit. So far, we have identified the protein ARC40 as essential for the formation of functional male gametes. When ARC40 is knocked out in the rodent parasite Plasmodium berghei, male gametes have a reduced DNA content and parasites can no longer successfully infect mosquitoes. ARC40 is thus important to segregate complete chromosome sets into the exiting male gametes. However, the mode of action of ARC40 and the mechanistic details of this process remain unclear. Since WD40 proteins often mediate protein-protein interactions, we hypothesise that ARC40 acts as a scaffold for a larger protein complex that connects chromosomes to gametes during their exit. Our goal is to characterise this protein complex by identifying the proteins that interact with ARC40. Furthermore, we want to investigate whether the mechanisms of chromosome segregation are conserved in the human-infecting species Plasmodium falciparum. ARC40 has been annotated as an actin-regulatory protein, and several published studies indicate a role for nuclear actin in chromosome segregation in a variety of organisms. In our final objective, we therefore aim to investigate the role of nuclear actin in Plasmodium gamete chromosome division. Here we focus in particular on a Plasmodium-specific actin isotype that is specifically present in male gametocytes. Fulfilling these three objectives will reveal new mechanisms for how Plasmodium coordinates DNA segregation with cell division during male gamete exit. If ARC40 is also essential for P. falciparum infection, these mechanisms could be a promising new drug target.