Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling by Plasmodium falciparum.

Abstract

Plasmodia are host-specific, both at the organism and cellular levels. During asexual development, Plasmodium spp. infect cells of erythroid lineage, with an overall propensity towards reticulocytes. This applies to even Plasmodium (P.) falciparum, the most common causative agent of human malaria, implications of which remain unexplored. Herein, for the first time, we characterize the developmental stages and features of P. falciparum cultured in vitro in young reticulocytes (CD71+) in comparison to standard normocyte (CD71-) cultures. We demonstrate that there are notable differences in the patterns of invasion, development and sensitivity to potent antimalarials (such as artemisinin and dihydroartemisinin) for parasites residing in CD71+ reticulocytes. Through a transcriptomic approach, we report that P. falciparum parasites are able to sense the host cell environment, and calibrate their metabolic and host cell remodelling pathways through differential gene expression. These results form an exciting avenue on which hitherto unexplored interactions between Plasmodium spp and different stages of host red blood cells could be investigated in the broader contexts of drug resistance, host tropism and zoonosis. Author SummaryParasites causing malaria infect red blood cells for development and proliferation during asexual development. This asexual erythrocytic stage determines higher parasite densities and eventual disease manifestation. Although the most virulent species of Plasmodium infecting humans known as Plasmodium falciparum is able to infect red blood cells of all ages, these parasites show a preference for younger blood cells. Of note, the biochemical and biophysical properties of young and adult red blood cells vary significantly. Herein, we undertook a comparative profiling of invasion process, parasite development and drug response of Plasmoddium falciparum in two host cells: young red blood cells (reticulocytes) and mature red blood cells (normocytes). We demonstrate that P. falciparum infects human reticulocytes with higher affinity and demonstrate differential sensitivity to drugs such as artemisinin while they reside within reticulocytes. Furthermore, we show that P. falciparum is able to detect differences in host environment and adapt to it by changing the expression of genes required for host cell remodelling.