Shedding light on malaria hypnozoites: Dissecting dormancy and activation

Abstract

In vivax-type malaria, "dormant" forms of the malaria parasite, known as hypnozoites, can settle in the liver. After prolonged periods of time, these forms can activate, which may cause renewed disease and transmission through the mosquito. This complicates the elimination of malaria and therefore new drugs are urgently needed against this latent parasite stage. However, virtually nothing is known about the biology of hypnozoites. Due to the lack of an in vitro culture system for the parasite forms required for transmission, the vivax-type parasites that cause malaria in humans are difficult to study. The closely related monkey malaria parasite Plasmodium cynomolgi offers a more accessible hypnozoite research model. The research described in this thesis has been performed with this parasite. The aim of this thesis was to map the genetic properties of hypnozoites and to use this knowledge to optimize drug assays for screening hypnozoite-killing compounds. In order to study these rare forms, we introduced DNA into the parasite to enable the visualization and purification of hypnozoites. Genetic characterization of hypnozoites revealed that these stages become progressively dormant over time. Only certain core processes remain active. We showed that these parasites can nevertheless ‘awaken’ in culture and continue their growth. Moreover, using DNA technology, we were able to detect hypnozoites in culture in a fast and sensitive manner. This will enable screening of hypnozoite-killing compounds at a larger scale.