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, 7 (9), 1427-42

Severe Malarial Anemia: Innate Immunity and Pathogenesis


Severe Malarial Anemia: Innate Immunity and Pathogenesis

Douglas J Perkins et al. Int J Biol Sci.


Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naïve infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naïve African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naïve children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.

Keywords: Innate Immunity; Malarial Anemia; Pathogenesis.

Conflict of interest statement

Conflict of Interests: The authors have declared that no conflict of interest exists.


Figure 1
Figure 1
Proposed Model of Dysregulation in Innate Immune Responses in Severe Malarial Anemia. Based on concomitant measurement of innate inflammatory mediators (using multiplex technologies) in children with varying severities of malarial anemia, we developed a model to describe how dysregulation in innate inflammatory mediators promotes suppression of erythropoiesis in children with SMA. Central to the model is the fact that phagocytosis of hemozoin (PfHz) by monocytes is one of the primary causes of altered production of innate inflammatory mediators. Elevated inflammatory mediators are shown in green text, while those that are decreased in children with SMA are shown in red text. Solid lines indicate positive signaling (up-regulation), whereas dashed lines indicate suppression (down-regulation). Children with SMA have decreased levels of IL-12 in response to ingestion of parasitized red blood cells (pRBC) and/or hemozoin by monocytes. Suppression of IL-12 in children with SMA is due to PfHz-induced IL-10 over-production. Children with SMA have increased circulating levels of TNF-α, IFN-γ, IL-6, MIP-1α, and MIP-1β. Although TNF-α can induce PGE2 and nitric oxide (NO), these effector molecules are suppressed in children with SMA. Suppression of PGE2 allows over-production of TNF-α, which is associated with enhanced severity of anemia. In addition, MIF is suppressed in children with falciparum malaria, an event associated with phagocytosis of PfHz by monocytes, and enhanced severity of anemia. Circulating levels of IFN-α, IL-1β, RANTES, and SCGF are also decreased in children with SMA. Reduced production of these innate inflammatory mediators, along with increased TNF-α, IL-6, MIP-1α and MIP-β, likely contribute to the development of SMA by suppressing the erythropoietic response. Lastly, although the reduced NO and reactive oxygen species (ROS) generation reported in children with falciparum malaria may promote ineffective parasite killing and, thereby, prolong parasitemia, children with malarial anemia have elevated levels of NO and ROS that can directly inhibit erythropoiesis.

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