The influence of host genetics on erythrocytes and malaria infection: is there therapeutic potential?

Lelliott et al. Malar J (2015) 14:289 DOI 10.1186/s12936-015-0809-x Open Access REVIEW The influence of host genetics on erythrocytes and malaria infection: is there therapeutic potential? Patrick M Lelliott*, Brendan J McMorran, Simon J Foote and Gaetan Burgio Abstract As parasites, Plasmodium species depend upon their host for survival. During the blood stage of their life-cycle parasites invade and reside within erythrocytes, commandeering host proteins and resources towards their own ends, and dramatically transforming the host cell. Parasites aptly avoid immune detection by minimizing the exposure of parasite proteins and removing themselves from circulation through cytoadherence. Erythrocytic disorders brought on by host genetic mutations can interfere with one or more of these processes, thereby providing a measure of protection against malaria to the host. This review summarizes recent findings regarding the mechanistic aspects of this protection, as mediated through the parasites interaction with abnormal erythrocytes. These novel findings include the reliance of the parasite on the host enzyme ferrochelatase, and the discovery of basigin and CD55 as obligate erythrocyte receptors for parasite invasion. The elucidation of these naturally occurring malaria resistance mechanisms is increasing the understanding of the host-parasite interaction, and as discussed below, is providing new insights into the development of therapies to prevent this disease. Keywords: Malaria, Plasmodium, Host, Polymorphism, Erythrocyte, Red blood cell, Invasion, Growth, Cytoadherence, Phagocytosis Background The clinical symptoms of malaria occur during the blood stage of Plasmodium’s life cycle. Safely ensconced within the host erythrocyte, parasites develop and replicate whilst concealing their presence from the immune system. After consuming the contents of the host cell, and growing and multiplying to fill the available space, the progeny egress as merozoites, and, after briefly existing extracellularly, invade fresh erythrocytes, continuing the cycle of growth and proliferation. This cycle depends on an elaborate interplay between host and parasite proteins, which has been meticulously established over thousands of years of co-evolution. As such, any perturbations to the composition or arrangement of proteins in the host erythrocyte can potentially impede the parasite’s growth and survival, and thereby increase the resistance of the *Correspondence: John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia host to infection. Indeed, abnormalities of the erythrocyte are relatively common, especially in populations residing in malaria-endemic regions, consistent with the positive selection for these conditions. The mechanistic basis for protection against malaria is partly understood in some abnormalities; parasite invasion and intraerythrocytic development are often affected. However, recent studies have revealed a more complex picture, with many conditions sharing multiple and over-lapping pathways that advantage the host. The understanding of the parasite-erythrocyte interaction is also being challenged as novel and highly intimate relationships between the parasite and its host cell are discovered. This review will summarize the current knowledge regarding Plasmodium’s interaction with abnormal host erythrocytes, the mechanisms by which these abnormalities can inhibit the blood stage of Plasmodium’s life cycle, and the implications of these findings for malaria treatment. © 2015 Lelliott et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lelliott et al. Malar J (2015) 14:289 Genetic erythrocyte abnormalities and malaria susceptibility Erythrocytes have a limited lifespan (120 days in humans) and, therefore, must be continually replenished in a process known as erythropoiesis. In this process haematopoietic stem cells replicate and differentiate into erythroblasts, and following expulsion of their nucleus and most organelles, develop into reticulocytes. Reticulocytes are released from the bone marrow into the bloodstream and following further depletion of organelles and intracellular RNA, become mature erythrocytes. There are a number of erythrocyte disorders that result from mutations in the genes expressed during erythropoiesis; many are highly prevalent, particularly in populations with a long history of malaria exposure. It was first observed nearly 70 years ago that people with ‘sickled’ erythrocytes were less likely to suffer from malaria [1]. This condition is common in various West and Central African ethnicities. Now known as sickle cell trait, this and many other erythrocytic disorders, have been strongly associated with reduced malaria susceptibility. In fact, mutations causing erythrocyte abnormalities are the most commonly observed genetic traits in humans [2]. Genetic mutations associated with malaria resistance have been extensively reviewed previously [3–5]; a summary of known erythrocytic genetic disorders and their association with malaria susceptibility is given in Table 1. Mechanisms by which erythrocyte abnormalities protect against malaria Early studies towards identifying malaria protective mechanisms imparted by erythrocyte abnormalities largely focussed on the ability of the parasite to invade and grow within erythrocytes. These studies were facilitated by an in vitro culturing system for Plasmodium falciparum, which allowed researchers to easily compare between erythrocytes obtained from subjects with various genetic conditions. As the understanding of malaria pathogenesis was expanded, the importance of factors such as cytoadherence and the ability of the immune system to detect parasitized erythrocytes was also recognized. Studies then addressed how erythrocyte abnormalities could affect not only parasite invasion and growth under in vitro conditions, but also their effects in vivo, and how this may influence host resistance to malaria infection. This review considers how specific erythrocyte abnormalities affect four distinct features of the parasite-host interaction. Namely, merozoite invasion, parasite growth, cytoadherence, and erythrocyte senescence. Merozoite invasion of the erythrocyte The brief interval between parasite egress and reinvasion of a new erythrocyte has long been considered a potential Page 2 of 15 weak point in its blood stage lifecycle. In vitro studies ha (...truncated)