Aim:
Effective antimalarials such as artesunate cause a rapid decline in the circulating parasite density of infected individuals. Antimalarials are thought to induce faster host removal of infected cells contributing to these rapid declines in infected cells. However, no comparison of the host removal of infected cells before and after treatment have been conducted.
Method:
Here, we employed a murine adoptive transfer system in which a single generation of labelled Plasmodium berghei parasitised RBCs (pRBCs) were transfused into recipient mice. This protocol allows us to track the loss of the transfused generation of parasites from circulation (as they are removed by the host or as mature stages rupture), and the appearance of their progeny in unlabelled recipient RBCs. We developed a mathematical model to directly estimate host clearance of pRBC during untreated infection, and after drug-treatment in mice.
Results:
We showed that in untreated mice, pRBCs were removed from circulation with a half-life of 14.7 hours suggesting that a substantial proportion of all pRBCs, ~70%, were removed before reaching maturity. The effect of drugs on the host removal of pRBCs was also explored by treating the mice with either artesunate or mefloquine. With an exception of high-dose artesunate treatment, which doubled the rate of pRBC removal (half-life of 8.7 hours), treatment with various doses of mefloquine or artesunate did not alter the rate of pRBC removal, despite blocking parasite replication effectively.
Lastly, to assess the role of phagocytes in the removal of pRBCs, we used clodronate-containing liposomes to deplete phagocytes or splenectomy. Both clodronate treatment and splenectomy reduced the rate of pRBC removal during untreated infection (half-life: 33.8 hours and 20.1 hours, respectively). A similar increase in half-life was observed in treated animals.
Conclusion:
Our work provides new insights into the role of parasite clearance following antimalarial drug treatment.