There are 5 malaria parasite (Plasmodium) species that infect humans, of which P. falciparum and P. vivax are the most important. P. vivax uniquely forms dormant parasite stages in the liver, called hypnozoites. Hypnozoites are only formed in 5 primate malarias (including 2 human malarias) and we use P. cynomolgi, that infects rhesus monkeys, as a model for P. vivax to study hypnozoites and discover new drugs that are urgently needed to kill hypnozoites. For this we have developed an in vitro liver stage culture system for P. cynomolgi.

Improving drug screening for dormant malaria parasites

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In 2019, we screened a small preselected chemical compound library of over 500 compounds for activity on P. cynomolgi liver stages, including hypnozoites. While data are still being analysed and confirmed, we found some 8% of the compounds having activity against developing and/or dormant liver stages. In a large collaborative study, we contributed to the development of an in vitro culture system for P. cynomolgi blood stage parasites. Although the parasite strain used may not be particularly suited for liver stage research, this work raises hope that in the future we may not need to infect monkeys anymore to supply us with blood stage parasites for further studies. In another collaboration we identified a protein, expressed during the liver stages and marking the point when liver stage parasites start to grow. Thus, this protein is not expressed in hypnozoites. We are currently using this information to develop new parasite lines that differentially express different enzymes in hypnozoites and growing liver stages. Such parasites will be used to develop enzymatic read out in more optimal in vitro drug assays. Read more >

 

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Detecting the presence of dormant malaria parasites

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Currently there is no diagnostic test to detect hypnozoites in the human population. Such a diagnostic test would be very useful at the time we want to wipe out hypnozoites from the population with new drugs, because it would identify individuals that need treatment. Together with Japanese colleagues, using our in vitro P. cynomolgi hypnozoite culture, we are working to pioneer development of a diagnostic test. In large scale experiments, covering many different variables, we identified a promising signature of molecules that seem to signal that host liver cells are infected with hypnozoites. The next step is to determine whether these molecules can also be detected in a hypnozoite-infected monkey.

 

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