Accounting for red blood cell accessibility reveals distinct invasion strategies in Plasmodium falciparum strains

The growth of the malaria parasite Plasmodium falciparum in human blood causes all the symptoms of malaria. To proliferate, non-motile parasites must have access to susceptible red blood cells, which they invade using pairs of parasite ligands and host receptors that define invasion pathways. Parasites can switch invasion pathways, and while this flexibility is thought to facilitate immune evasion, it may also reflect the heterogeneity of red blood cell surfaces within and between hosts. Host genetic background affects red blood cell structure, for example, and red blood cells also undergo dramatic changes in morphology and receptor density as they age. The in vivo consequences of both the accessibility of susceptible cells, and their heterogeneous susceptibility, remain unclear. Here, we measured invasion of laboratory strains of P. falciparum relying on distinct invasion pathways into red blood cells of different ages. We estimated invasion efficiency while accounting for red blood cell accessibility to parasites. This approach revealed different tradeoffs made by parasite strains between the fraction of cells they can invade and their invasion rate into them, and we distinguish "specialist" strains from "generalist" strains in this context. We developed a mathematical model to show that generalist strains would lead to higher peak parasitemias in vivo compared to specialist strains with similar overall proliferation rates. Thus, the ecology of red blood cells may play a key role in determining the rate of P. falciparum parasite proliferation and malaria virulence. Author summary The growth of the malaria parasite Plasmodium falciparum in human blood causes all the symptoms of malaria. Parasites invade red blood cells using pathways defined by a parasite ligand and a corresponding host receptor. As red blood cells age, they undergo changes, affecting which pathways can be used by parasites for invasion. We studied laboratory parasites relying on distinct pathways and measured their ability to invade red blood cells of different ages. We found that parasites trade-off between the proportion of red blood cells they can invade and the efficiency of the invasion process. Using a mathematical model, we predict that these trade-offs affect parasite growth in vivo, with important consequences for virulence.