Quantification of host-mediated parasite clearance during blood-stage Plasmodium infection and anti-malarial drug treatment in mice

Within‐host modeling of blood‐stage malaria

“…Hence, by looking at the number of endogenous RBCs that become parasitized over time we can track the appearance of the progeny of Gen 0 pRBCs (Figure B and C). We constructed a statistical model that looked at the magnitude of the loss of donor (labeled) pRBCs over a given time step and the corresponding appearance of unlabeled parasitized RBCs in order to estimate the number of pRBCs that were lost due to rupture and those that were lost due to host removal . This modeling gave an estimate that pRBCs were removed with a 15 hour half‐life in naive mice (no previous infection), ie, on average 68% of all parasites are removed before they can reach maturity and rupture …”

“…Most models of drug action in malaria combine the two processes of drug killing of parasites, and the subsequent removal of those killed parasites, by assuming instantaneous removal (Figure A) . However, several studies have proposed that drug killing of parasites and their removal might be two separate processes, and that the rate of killing might be faster than the rate of clearance of those killed parasites by the host (Figure B) . Under this scenario, the presence of drug for 6 hours may be sufficient to kill parasites (or perhaps to “stun” them, since they may appear morphologically normal).…”

“…This study indicates that drug action to impair or kill pRBCs is very rapid (complete within 6 hours), but that the subsequent host removal of these impaired or killed parasites is considerably slower. The removal of these drug‐affected parasites appeared host‐mediated, as removal of phagocytes by clodronate treatment, or splenectomy, significantly reduced the clearance rate . This strongly suggests that models should be incorporating drug effect and pRBC clearance as separate processes in vivo.…”

“…106 We recently developed a novel adoptive transfer assay to assess parasite clearance in which blood from infected donor mice is labeled with a fluorescent cytoplasmic dye and transfused into recipient mice ( Figure 8A). 48,[131][132][133] A portion of the labeled RBCs are parasitized, allowing us to track, by flow cytometry, a single labeled generation of pRBCs and monitor their disappearance and clearance in a group of recipient mice ( Figure 8B and C). We call this labeled generation of pRBCs Gen 0 parasites.…”

“…15,16,44,74 However, several studies have proposed that drug killing of parasites and their removal might be two separate processes, and that the rate of killing might be faster than the rate of clearance of those killed parasites by the host ( Figure 14B). 132,133,138,183,[193][194][195] Under this scenario, the presence of drug for 6 hours may be sufficient to kill parasites (or perhaps to "stun" them, since they may appear morphologically normal). These drug-affected (unviable) parasites remain in circulation and are subsequently cleared at an exponential rate ( Figure 14B).…”