Reductions of the total circulating parasite density after drug treatment or immunity is referred to as clearance. It is often thought this clearance of the total parasite density is due to host removal of circulating infected cells. Therefore we set out to determine what contribution host removal of infected cell made to the overall control of infection after drug treatment, and through host innate and acquired immune responses.
We directly measured host removal of parasites using a novel adoptive transfer protocol. This involved transferring fluorescently labelled parasitised red blood cells (pRBCs) from infected donor mice into recipient mice, and then tracking the loss of these labelled donor pRBCs with intensive sampling over 24 or 48 hours. Novel mathematical modelling approaches were developed to analyse this data. We studied the contribution of clearance in controlling acute infection, infection after drug treated and infection in immune mice.
We estimated the clearance half-life of P. berghei infected cells in naïve mice (14.4h). However, we also investigated parasite clearance by innate and acquired host immune responses, and found that, despite controlling infection, neither induced faster removal of pRBCs by the host. Interestingly, innate immune responses during acute P. berghei infection, rather than increasing removal of pRBCs, caused pRBCs to mature more slowly. Even after treatment with an antimalarial such as mefloquine, host removal of pRBCs was not increased compared with the control group. Only after high dose artesunate treatment did we observe faster host removal of pRBCs.
Our work demonstrates a high basal rate of pRBC clearance in naïve mice, but that this is not easily increased by host responses or drug treatment, providing new insight into the role of parasite clearance in malaria infection.