Mechanisms of Splenic Control of Murine Malaria: Tissue Culture Studies of the Erythropoietic Interplay of Spleen, Bone Marrow, and Blood in Lethal (Strain 17XL) Plasmodium Yoelii Malaria in BALB/c Mice

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  • School of Veterinary Medicine, University of Pennsylvania; and Hahnemann University School of Medicine, Philadelphia, Pennsylvania
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This work characterizes the erythropoietic interplay of the spleen, blood, and bone marrow in a lethal murine malaria, strain 17XLP. yoelii. This malaria runs a fulminant 7 day course in BALB/c/ByJ mice, marked by high levels of parasitized reticulocytes with death likely due to anemia. We have quantitated the levels of burst forming units-erythroid (BFU-E), the early, niche-seeking, largely erythropoietin-unresponsive erythropoietic precursors, and of colony forming units-erythroid (CFU-E), the more differentiated sessile erythropoietin-responsive precursors, in bone marrow, blood, and spleen, through the course of this malaria.

A decline in marrow BFU-E began on day 2, but recovered, relatively, after day 3. Marrow cellularity declined, being but 75% normal on day 6. Spleen weight increased about 5-fold within 6 days with enlargement of erythroid, lymphoid, macrophage, and stromal compartments. Splenic BFU-E increased in the first 24 hr and 5-fold by day 6. Splenic CFU-E increased in the first 24 hr and into day 4. They then declined and showed a secondary, large-scale, sustained rise interrupted by death. Because the spleen was enlarging, a >60-fold increase in the absolute number of splenic CFU-E occurred at the time of death. Marrow CFU-E followed the same pattern as splenic CFU-E, but the terminal increase represented but a 4-fold absolute increase because of declining marrow cellularity.

High levels of erythropoietin occurred only late in the course of disease, likely in response to profound anemia. The splenic (but not the marrow) erythropoiesis that occurred within 24 hr of the outset of disease, before the development of any anemia, was stimulated by the serum of malarial animals. Erythropoietin administered to normal animals stimulated marrow erythropoiesis but failed to stimulate splenic erythropoiesis. Splenic erythropoiesis, therefore, is not simply an extramedullary spill-over, but governed by factors different from those that control bone marrow.