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.