Malaria, erythrocytic infection, and anemia

Abstract

Malaria is a major world health problem. It results from infection of parasites belonging to the genus Plasmodium. Plasmodium falciparum and Plasmodium vivax cause the major human malarias, with P falciparum being the more virulent. During their blood stages of infection, both P falciparum and P vivax induce anemia. Severe malarial anemia caused by P falciparum is responsible for approximately a third of the deaths associated with disease. Malarial anemia appears to be multi-factorial. It involves increased removal of circulating erythrocytes as well as decreased production of erythrocytes in the bone marrow. The molecular mechanisms underlying malarial anemia are largely unknown. Over the last five years, malaria parasite ligands have been investigated for their remodeling of erythrocytes and possible roles in destruction of mature erythrocytes. Polymorphisms in cytokines have been associated with susceptibility to severe malarial anemia: these cytokines and malaria "toxins" likely function by perturbing erythropoiesis. Finally a number of co-infections increase susceptibility to malarial anemia, likely because they exacerbate inflammation caused by malaria. Because of the complexities involved, the study of severe malarial anemia may need a "systems approach" to yield comprehensive understanding of defects in both erythropoiesis and immunity associated with disease. New and emerging tools such as (i) mathematical modeling of the dynamics of host control of malarial infection, (ii) ex vivo perfusion of human spleen to measure both infected and uninfected erythrocyte retention, and (iii) in vitro development of erythroid progenitors to dissect responsiveness to cytokine imbalance or malaria toxins, may be especially useful to develop integrated mechanistic insights and therapies to control this major and fatal disease pathology.

Figure 1. Malarial anemia: a model for the role of parasite ligands and dynamics of the host immune and erythropoietic response

A. A schematic of blood stage parasite infection. Extracellular merozoites contain specialized organelles called the rhoptries, micronemes and dense granules. Parasite proteins (blue orange and red dots) from these organelles are delivered to the junction of invasion (that concentrates rafts shown in blue) between the merozoite and the erythrocyte. Invasion is a rapid, highly inefficient process and thus may be aborted but nonetheless result in antigen deposition on the erythrocyte. Parasites that become intracellular continue to secrete proteins to remodel the erythrocyte as they mature (for 48 hours for Plasmodium falciparum). When infected erythrocytes rupture, parasite proteins are released in plasma. Parasite protein release in plasma also occurs when merozoites fail to invade erythrocytes. A subset of these are erythrocyte adhesive and may deposit on uninfected erythrocytes to change their antigenic and vascular properties. B. 1). Uninfected and infected erythrocytes remodelled by parasite as shown in panel A may be filtered by the spleen. This could be due to mechanical filtration as well as an inflammatory response. 2). Nurse cell macrophages secrete cytokines that are critical to maturation of erythrocytes. Stimulation of Th1 as well as (unexpectedly) Th2 cytokines like IL4, by multiple components shown in panel A, may promote diserythropoiesis. 3 and 4). Antibody production and coinfections could modulate both splenic and macrophage functions and thus exacerbate anemia. C. Initial modelling studies suggest that events triggered in A create imbalance in both the immune and hematopoietic responses shown in B, such that both must be restored to overcome this complex disease pathology.