Increasing evidence critically implicates miRNAs in the pathogenesis of diseases, but little is known in context with infectious diseases. This study investigates as to whether the testosterone-induced persistent susceptibility to blood-stage malaria of Plasmodium chabaudi coincides with changes in miRNA expression of the anti-malaria effectors sites spleen and liver. Female C57BL/6 mice were treated with vehicle or testosterone (T) for 3 weeks. Then, T treatment was discontinued for 12 weeks before challenge with 10(6) P. chabaudi-parasitized erythrocytes. The miRNA expression was examined after 12 weeks of T withdrawal and during infections at peak parasitemia on day 8 p.i. using miRXplore™ microarray technology. P. chabaudi infections induce an organ-specific response of miRNA expression. We can identify 25 miRNA species to be downregulated by more than 2-fold in the spleen and 169 miRNA species in the liver. Among these 194 miRNA species, there are 12 common miRNA species that are downregulated by 0.48-0.14-fold in both spleen and liver, which are miR-194, miR-192, miR-193A-3P, miR-145, miR-16, miR-99A, miR-99B, miR-15A, miR-152, let-7G, let-7B, and miR-455-3P. Only in the liver, there is an upregulation of the miR-142-5p by 2.5-fold and miR-342-3p by 5.1-fold. After 12 weeks of T withdrawal, the spleen exhibits only the miR-200A that is upregulated by 2.7-fold. In the liver, miR-376B, miR-493*, and miR-188-3P are upregulated by 2.4-fold, 2.2-fold, and 2.1-fold, respectively, and miR-347, miR-200A, and miR-200B are downregulated by approximately 0.4-fold. Upon infection, however, these changes are not sustained, i.e., the miRNA expressions of both spleen and liver of T-pretreated mice exhibit the same response to P. chabaudi malaria as that of vehicle-treated control mice. Our data suggest (1) that the P. chabaudi-induced downregulation of miRNA expression in spleen and liver is required to allow the upregulation of their numerous target genes in response to infection, and (2) that the T-induced persistent susceptibility to P. chabaudi does not affect the responsiveness of miRNA expression in spleen and liver to blood-stage malaria.
Erythropoiesis and megakaryo-/thrombopoiesis occur in the bone marrow proceeding from common, even bipotent, progenitor cells. Recently, we have shown that protective vaccination accelerates extramedullary hepatic erythroblastosis in response to blood-stage malaria of Plasmodium chabaudi. Here, we investigated whether protective vaccination also accelerates extramedullary hepatic megakaryo-/thrombopoiesis. Female Balb/c mice were twice vaccinated with a non-infectious vaccine before infecting with 106 P. chabaudi-parasitized erythrocytes. Using gene expression microarrays and quantitative real-time PCR, transcripts of genes known to be expressed in the bone marrow by cells of the megakaryo-/thrombocytic lineage were compared in livers of vaccination-protected and unprotected mice on days 0, 1, 4, 8, and 11 p.i. Livers of vaccination-protected mice responded with expression of megakaryo-/thrombocytic genes faster to P. chabaudi than those of unvaccinated mice, evidenced at early patency on day 4 p.i., when livers exhibited significantly higher levels of malaria-induced transcripts of the genes Selp and Pdgfb (p-values < 0.0001), Gp5 (p-value < 0.001), and Fli1, Runx1, Myb, Mpl, Gp1ba, Gp1bb, Gp6, Gp9, Pf4, and Clec1b (p-values < 0.01). Together with additionally analyzed genes known to be related to megakaryopoiesis, our data suggest that protective vaccination accelerates liver-intrinsic megakaryo-/thrombopoiesis in response to blood-stage malaria that presumably contributes to vaccination-induced survival of otherwise lethal blood-stage malaria.
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