Abstract
Severe malaria anemia is one of the most common causes of morbidity and mortality arising from infection with Plasmodium falciparum. The pathogenesis of malarial anemia is complex, involving both parasite and host factors. As mouse models of malaria also develop anemia, they can provide a useful resource to study the impact of Plasmodium infections and the resulting host innate immune response on erythropoiesis. In this study, we have characterized the bone marrow and splenic responses of the erythroid as well as other hematopoietic lineages after an acute infection of Balb/c mice with Plasmodium berghei. Such characterization of the hematopoietic changes is critical to underpin future studies, using knockout mice and transgenic parasites, to tease out the interplay between host genes and parasite modulators implicated in susceptibility to malaria anemia. P. berghei infection led to a clear perturbation of steady-state erythropoiesis, with the most profound defects in polychromatic and orthochromatic erythroblasts as well as erythroid colony- and burst-forming units (CFU-E and BFU-E), resulting in an inability to compensate for anemia. The perturbation in erythropoiesis was not attributable to parasites infecting erythroblasts and affecting differentiation, nor to insufficient erythropoietin (EPO) production or impaired activation of the Signal transducer and activator of transcription 5 (STAT5) downstream of the EPO receptor, indicating EPO-signaling remained functional in anemia. Instead, the results point to acute anemia in P. berghei-infected mice arising from increased myeloid cell production in order to clear the infection, and the concomitant release of pro-inflammatory cytokines and chemokines from myeloid cells that inhibit erythroid development, in a manner that resembles the pathophysiology of anemia of chronic disease.
Highlights
Malaria is a global health problem caused by infection with parasites belonging to the genus Plasmodium
We examined the erythropoietic and wider hematopoietic responses that occur in the bone marrow and spleen of Balb/c mice after an acute infection with Plasmodium berghei, a rodent malaria strain which is most widely used for gene knockout studies
Mice were infected with wild-type P. berghei ANKA and P. berghei EXP2-2A-FRT, the latter expressing an exported GFP reporter (KAHRPL-GFP), in which the sequence of KAHRP (P. falciparum knob-associated histidine-rich protein) that directs export into the host red blood cells (RBCs) is fused in frame to GFP, under the transcriptional control of the HSP70 promoter (Kalanon et al, 2016)
Summary
Malaria is a global health problem caused by infection with parasites belonging to the genus Plasmodium. Clinical evaluation of patients with SMA has revealed this pathology is characterized by significantly lower numbers of erythroid colony-forming cells [ the burst forming units (BFU-E)], premature death of erythroblasts and low reticulocytosis (Wickramasinghe et al, 1982; Maggio-Price et al, 1985; Abdalla and Wickramasinghe, 1988; Jootar et al, 1993) It remains unclear whether deficiency of EPO is a major contributor to inadequate erythropoiesis in malaria. We examined the erythropoietic and wider hematopoietic responses that occur in the bone marrow and spleen of Balb/c mice after an acute infection with Plasmodium berghei, a rodent malaria strain which is most widely used for gene knockout studies Such characterization is critical to underpin future studies to tease out and validate the interplay between parasite modulators and host genes that determine susceptibility to malaria anemia that have, for example, been identified through human genome wide association studies
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