Revealing mechanisms underlying variation in malaria virulence: effective propagation and host control of uninfected red blood cell supply.

Malaria parasite clones with the highest transmission rates to mosquitoes also tend to induce the most severe fitness consequences (or virulence) in mammals. This is in accord with expectations from the virulence-transmission trade-off hypothesis. However, the mechanisms underlying how different clones cause virulence are not well understood. Here, using data from eight murine malaria clones, we apply recently developed statistical methods to infer differences in clone characteristics, including induction of differing host-mediated changes in red blood cell (RBC) supply. Our results indicate that the within-host mechanisms underlying similar levels of virulence are variable and that killing of uninfected RBCs by immune effectors and/or retention of RBCs in the spleen may ultimately reduce virulence. Furthermore, the correlation between clone virulence and the degree of host-induced mortality of uninfected RBCs indicates that hosts increasingly restrict their RBC supply with increasing intrinsic virulence of the clone with which they are infected. Our results demonstrate a role for self-harm in self-defence for hosts and highlight the diversity and modes of virulence of malaria.