Malaria parasites and red cell variants: when a house is not a home

Abstract

Purpose of review: Multiple red cell variants are known to confer protection from malaria. Here, we review advances in identifying new variants that modulate malaria risk and in defining molecular mechanisms that mediate malaria protection.

Recent findings: New red cell variants, including an innate variant in the red cell's major Ca²⁺ pump and the acquired state of iron deficiency, have been associated with protection from clinical falciparum malaria. The polymorphisms hemoglobin C (HbC) and hemoglobin S (HbS) - known to protect carriers from severe falciparum malaria - enhance parasite passage to mosquitoes and may promote malaria transmission. At the molecular level, substantial advances have been made in understanding the impact of HbS and HbC upon the interactions between host microRNAs and Plasmodium falciparum protein translation; remodeling of red cell cytoskeletal components and transport of parasite proteins to the red cell surface; and chronic activation of the human innate immune system, which induces tolerance to blood-stage parasites. Several polymorphisms have now been associated with protection from clinical vivax malaria or reduced Plasmodium vivax density, including Southeast Asian ovalocytosis and two common forms of glucose-6-phosphate dehydrogenase deficiency.

Summary: Red cell variants that modulate malaria risk can serve as models to identify clinically relevant mechanisms of pathogenesis, and thus define parasite and host targets for next-generation therapies.

Figure 1. Diverse mechanisms by which red cell variants may influence malaria pathogenesis

A. Plasmodium spp. parasites invade, mature, and replicate in red cells, and these events may be disrupted by a variety of mechanisms including the influence of host microRNAs on parasite protein translation, as described by LaMonte et al. (34). B. P. falciparum-infected red cells cause disease by binding to extracellular receptors on the surface of microvascular endothelial cells, uninfected red cells, and placental syncytiotrophoblasts via the parasite-derived surface antigen PfEMP1; trafficking of PfEMP1 to the red cell surface is impaired in HbS- and HbC-containing cells owing to a disruption of the parasite’s remodeling of the cell’s actin cytoskeleton, as described by Cyrklaff et al. (33). C. Activation of the innate immune system by infected red cells, parasite DNA, and free heme can alter the balance of pro- and anti-inflammatory cytokines to influence pathogenesis, as described by Ferreira et al. (41). These investigators propose that the chronic release of free heme from HbS-containing red cells activates heme oxygenase-1, which then mediates tolerance of Plasmodium parasites in a murine model of cerebral malaria. D. Plasmodium spp. parasites may be cleared more efficiently by the adaptive immune system when infecting red cell variants, though Tan et al. (40) report that children with β-globin variants did not acquire antibodies to P. falciparum proteins more rapidly or efficiently than children with normal β-globins. Originally published in Taylor SM, Cerami C, Fairhurst RM. Hemoglobinopathies: Slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis. PLoS Pathogens 2013;9:e1003327. Made available under the Creative Commons Attribution CCBY license.

Figure 2. Tolerance of Plasmodium falciparum hyperparasitemia

A 2-year-old Malian boy presented with a history of fever and malaise. Thick and thin blood films stained with Giemsa showed 273,450 parasites per µL of whole blood (A) and 25.7% parasitemia (B), respectively. At this time, he had a normal temperature (36.9°C) and moderate anemia (Hb level 7.8 g/dL). The child received artesunate and amodiaquine over 3 days, never developed symptoms or signs of severe malaria, and was later found to carry the sickle-cell trait. This case was originally published in Blood. Beaudry JT, Fairhurst RM. Microvascular sequestration of Plasmodium falciparum. Blood. 2011;117:6410. © the American Society of Hematology.