Targeting the Hypnozoites: Towards an in vitro System for Malaria Drug Discovery

Malaria still has a global incidence of about 219 million cases per year and the World Health Organization estimates that nearly half of the world’s population is at risk of the disease in 2017. The majority of the available antimalarials on the market exclusively target the asexual and proliferative stages of malaria parasites. However, to eliminate malaria, we will need drugs that prevent parasite transmission and eliminate the dormant liver stages found after infection with Plasmodium vivax (P. vivax) and Plasmodium ovale. These quiescent forms called hypnozoites can survive for months in the liver and reactivate into mature liver schizonts causing relapses in patients.
In order to elucidate the mechanisms underlying liver stage dormancy and to accelerate drug discovery for P. vivax malaria, we developed an in vitro infection model using stem cell-derived hepatocytes that allows studies of the hypnozoites. Considering the difficulties related to P. vivax in vitro work, the simian parasite Plasmodium cynomolgi, which also produces hypnozoites, was chosen as a surrogate model. Hepatocyte-like cells generated from induced pluripotent stem cells (iPS) derived from Macaca fascicularis were successfully infected with Plasmodium cynomolgi sporozoites and both hypnozoites and liver schizonts were observed for 12 days post infection.
This PhD thesis reports the development of a new iPS-based model that allows hypnozoite formation, overcomes the limitations of P. vivax and primary hepatocytes, and provides a promising and versatile model to investigate the dormant liver stage of malaria.