Accounting for red blood cell accessibility reveals distinct invasion strategies inPlasmodium falciparumstrains

Abstract

AbstractThe growth of the malaria parasitePlasmodium falciparumin human blood causes all clinical manifestations of malaria, a process that begins with the invasion of red blood cells. Parasites enter red blood cells using distinct pairs of parasite ligands and host receptors that define particular invasion pathways. Parasite strains have the capacity to switch between invasion pathways. This flexibility is thought to facilitate immune evasion against particular parasite ligands, but may also reflect the fact that red blood cell surfaces are dynamic and composed of heterogeneous invasion targets. Different host genetic backgrounds affecting red blood cell structure have long been recognized to impact parasite growthin vivo, but even within a host, red blood cells undergo dramatic changes in morphology and receptor density as they age. The consequences of these heterogeneities for parasite growthin vivoremain unclear. Here, we measured the ability of laboratory strains ofP. falciparumrelying on distinct invasion pathways to enter red blood cells of different ages. We estimated invasion efficiency while accounting for the fact that even if the red blood cells display the appropriate receptors, not all are physically accessible to invading parasites. This approach revealed a tradeoff made by parasites between the fraction of susceptible cells and their invasion rate into them. We were able to distinguish between “specialist” strains exhibiting high invasion rate in fewer cells versus “generalist” strains invading less efficiently into a larger fraction of cells. We developed a mathematical model to predict that infection with a generalist strain would lead to higher peak parasitemiasin vivowhen compared with a specialist strain with similar overall proliferation rate. Thus, the heterogeneous ecology of red blood cells may play a key role in determining the rate of parasite proliferation between different strains ofP. falciparum.