Inhibition of erythropoiesis by a soluble factor in murine malaria

To study the cellular mechanisms involved in the ineffective erythropoiesis associated with malaria, an in vitro proliferative assay was used to measure the response to erythropoietin (Epo) of erythroid progenitor cells from malaria-infected mice. In this assay, spleen (SP) cells from phenylhydrazine (PHZ)-treated mice (PHZ-SP), enriched for erythroid progenitor cells, respond to Epo in a dose-dependent manner. Despite a similar degree of anemia, SP and bone marrow (BM) cells from Plasmodium berghei- or P. vinckei-infected mice did not show a significant response to Epo in this assay. When SP or BM cells from malaria-infected mice were added to cultures of SP or BM cells from PHZ-treated mice the response to Epo of these cells was significantly inhibited. Removal of parasitized red blood cells (pRBC) from SP cells of P. berghei-infected mice had no effect on the ability of the cells to inhibit the response to Epo. Adherent SP cells and SP cells positive for the Mac-1 antigen, from malaria-infected mice, were shown to be enriched for cells that could inhibit the response to Epo. Cell-free conditioned media (CM) prepared from SP cells of P. berghei- or P. vinckei-infected mice or from normal SP cells incubated with pRBC were also able to inhibit the response to Epo of SP cells from PHZ-treated mice. These investigations have shown that during the course of malaria infection, cells appear in the SP and BM capable of inhibiting, via soluble mediators, the response to Epo of erythroid progenitor cells. The cells responsible are probably macrophages. The nature of the factor(s) and its mechanism of action are not known. Through the ability to inhibit erythropoiesis, soluble factors may, in part, mediate the anemia associated with malaria.