Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling byPlasmodium falciparum

Abstract

29Plasmodia are host-specific, both at the organism and cellular levels. During asexual 30 development, Plasmodium spp. infect cells of erythroid lineage, with an overall 31 propensity towards reticulocytes. This applies to even Plasmodium (P.) falciparum, the 32 most common causative agent of human malaria, implications of which remain 33 unexplored. Herein, for the first time, we characterize the developmental stages and 34 features of P. falciparum cultured in vitro in young reticulocytes (CD71 + ) in comparison to 35 standard normocyte (CD71 -) cultures. We demonstrate that there are notable differences 36 in the patterns of invasion, development and sensitivity to potent antimalarials (such as 37 artemisinin and dihydroartemisinin) for parasites residing in CD71 + reticulocytes. 38Through a transcriptomic approach, we report that P. falciparum parasites are able to 39 sense the host cell environment, and calibrate their metabolic and host cell remodelling 40 pathways through differential gene expression. These results form an exciting avenue on 41 which hitherto unexplored interactions between Plasmodium spp and different stages of 42 host red blood cells could be investigated in the broader contexts of drug resistance, 43 host tropism and zoonosis. 45Author Summary 46Parasites causing malaria infect red blood cells for development and proliferation during 47 asexual development. This asexual erythrocytic stage determines higher parasite 48 densities and eventual disease manifestation. Although the most virulent species of 49 Plasmodium infecting humans known as Plasmodium falciparum is able to infect red 50 blood cells of all ages, these parasites show a preference for younger blood cells. Of 51 note, the biochemical and biophysical properties of young and adult red blood cells vary 52 significantly. Herein, we undertook a comparative profiling of invasion process, parasite 53 development and drug response of Plasmoddium falciparum in two host cells: young red 54 blood cells (reticulocytes) and mature red blood cells (normocytes). We demonstrate that 55 P. falciparum infects human reticulocytes with higher affinity and demonstrate differential 56 3 sensitivity to drugs such as artemisinin while they reside within reticulocytes. 57Furthermore, we show that P. falciparum is able to detect differences in host 58 environment and adapt to it by changing the expression of genes required for host cell 59 remodelling. 61 Introduction 62Plasmodium infection and associated mortality remain an important concern to the 63 developing world with 218 million malaria cases and ~450,000 deaths annually 1 64 (https://www.who.int/malaria/publications/world-malaria-report-2018/en/). 65Widespread drug-resistance 2-3 and evolution of newer phenotypes; influenced by factors 66 such as changing availability and distribution of insect vector 4 , haematological 67 malignancies(1, 2) 5-6 (thalassemia, sickle cell anaemia, G6PD deficiency etc), providing 68 protective immunity to certain populations 7 , adversely impact malaria eradic...

Rodent Malaria Erythrocyte Preference Assessment by an Ex Vivo Tropism Assay

“…It is thought that the reason behind this strict tropism is because P. vivax can only invade via receptors that are only present on reticulocytes, and indeed, two such reticulocyte-specific receptors, CD71 and CD98, were identified recently ( Gruszczyk et al., 2018 ; Malleret et al., 2021 ). P. falciparum , the deadliest human malaria species, also has a preference for reticulocytes, but can invade normocytes too ( Pasvol et al., 1980 ; Naidu et al., 2019 ). However, no reticulocyte-specific receptor for P. falciparum invasion has been identified so far ( Cowman et al., 2017 ).…”

Erythrocyte tropism of malarial parasites: The reticulocyte appeal

“…Most tropism studies on P. falciparum agree that it has the capability to invade both reticulocytes and normocytes but prefers reticulocytes when available ( Table 1 ). Varying extents of its reticulocyte preference were reported: from as low as 2 times more ( Pasvol et al, 1980 ; Naidu et al, 2019 ), to as high as 14 times more ( Hegner, 1938 ) than its normocyte preference. While P. falciparum has a predilection for reticulocytes, P. vivax invasion is strictly restricted to reticulocytes, with an early report showing a 1,291-fold preference for reticulocytes over normocytes ( Hegner, 1938 ).…”

The Black Box of Cellular and Molecular Events of Plasmodium vivax Merozoite Invasion into Reticulocytes

“…P. falciparum , P. knowlesi and P. malariae Mrz invade mature erythrocytes, although P. falciparum and P. knowlesi can also invade reticulocytes [ 5 , 6 ], whilst P. vivax and P. ovale are restricted to invading reticulocytes [ 7 , 8 ]. Such immature cells represent only 1–2% of circulating RBCs, indicating that these two Plasmodium species’ Mrz have an as-yet-unknown mechanism to accurately target the reticulocyte population during invasion.…”