Effect of inherited red cell defects on growth of Plasmodium falciparum: An in vitro study.

BACKGROUND & OBJECTIVES: High prevalence of certain polymorphic alleles of erythrocytes in malaria endemic area has been linked to the resistance provided by these alleles against parasitic infestations. Numerous studies undertaken to demonstrate this correlation have generated conflicting results. This study was undertaken to investigate the abilities of various polymorphic erythrocytes to support in vitro growth of Plasmodium falciparum parasites. METHODS: In this study under in vitro condition the ability of P. falciparum parasites to grow was assessed in the erythrocytes obtained from a total of 40 patients with various haemoglobinopathies, such as ß-thalassaemia (ß-Thal), sickle cell anaemia, erythroenzymopathy-like glucose-6-phosphate dehydrogenase deficiency and membranopathy-like hereditary spherocytosis. RESULTS: Significantly reduced in vitro invasion and growth of parasites was seen in the cultures containing abnormal erythrocytes than in control cultures containing normal erythrocytes (P< 0.05). The mean per cent parasitaemia comparison was also carried out among the three polymorphic erythrocyte groups, i.e. ß-Thal, sickle cell anaemia and enzyme-membranopathies. INTERPRETATION & CONCLUSIONS: Erythroenzymopathies and membranopathies were found to provide a more hostile environment for parasites, as the least parasitaemia was observed in these erythrocytes. The present in vitro study showed that P. falciparum did not grow well and did not invade well in erythrocytes obtained from common inherited red cell disorders.

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

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.

Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.

Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits--including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia--are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.

Host actin remodeling and protection from malaria by hemoglobinopathies.

Many intracellular pathogens remodel the actin of their host cells, and the human malaria parasite Plasmodium falciparum is no exception to this rule. The surprising finding is that several hemoglobinopathies that protect carriers from severe malaria may do so by interfering with host actin reorganization. Here we discuss our current understanding of actin remodeling in P. falciparum-infected erythrocytes, how hemoglobinopathies interfere with this process, and how impaired host actin remodeling affects the virulence of P. falciparum.

Control of immunopathology during Plasmodium infection by hepcidin.

Malaria is a major health problem affecting millions of people annually especially in underdeveloped countries. Mutations causing alterations in hemoglobin production or structure are known to afford protection against the development of severe forms of malaria. Not surprinsingly, these hemoglobin disorders are present at high frequency in areas where malaria is endemic, indicating a survival advantage for individuals carrying them. Despite many years of research, the exact mechanisms underlying the protection afforded by hemoglobinopathies against severe forms of malaria have not yet found a definitive answer. One feature of hemoglobinopathies, observed both in humans and mice, is the fact that individuals carrying these disorders express low levels of the hormone hepcidin that plays a major role in iron homeostasis. Hepcidin acts by binding to the iron exporter ferroportin and inducing its degradation. When hepcidin levels are low, ferroportin expression in cells is sustained leading to export of intracellular iron. Importantly, low intracellular iron content may affect activation of innate immune cells leading to diminished production of pro-inflammatory cytokines. Notably, several lines of evidence support the notion that development of severe forms of malaria is dependent on immune-mediated damage, caused by unfettered immune responses. Herein the hypothesis that hemoglobinopathies afford protection against severe forms of malaria by limiting exacerbated immune activation, via a mechanism that involves low hepcidin expression, is discussed.

Red blood cell defects and malaria.

Malaria is a major cause of childhood death throughout much of the tropical world. As a result, it has exerted a powerful force for the evolutionary selection of genes that confer a survival advantage. Identifying which genes are involved, and how they affect malaria risk, is a potentially useful way of exploring the host-parasite relationship. To date, some of the best-described malaria-protective polymorphisms relate to genes that affect the structure or function of red blood cells (RBC). Recent years have seen significant advances in our understanding of the importance of some of these genes, including glycophorin C (GYPC); complement receptor 1 (CR1); band 3 (SLC4A1); pyruvate kinase (Pklr); and the genes for alpha-(HBA) and beta-globin (HBB). The challenge for the future must be to convert these advances into fresh approaches to the prevention and treatment of malaria.