Abstract
AbstractOur laboratory’s previous microarray analysis of subjects with Plasmodium falciparum revealed up-regulation of Toll-like receptor, NF-kB, TNF-α, IFN-γ, IL-1β, p38 MAPK, and MHC molecules. We performed further time-course microarray analysis focusing on malaria pathogenesis by using peripheral leukocytes as a cellular model. We found up-regulation of coagulation-related genes (SERPINB2, thrombomodulin, thrombospondin), heat shock proteins, glycolytic enzymes, glucose transporters, and vacuolar H+-ATPases in acute febrile malaria. In early malaria, prior to detectable parasitemia, CD36 and ICAM1 were up-regulated. During acute malaria, a correlation was observed between IL-1ß and heat shock proteins, suggesting heat shock protein response may be in the febrile response induced by IL-1ß. CD163, a hemoglobin scavenger receptor, was up-regulated in acute malaria to potentially facilitate free hemoglobin up-take by peripheral leukocytes. In acute malaria, high MafB gene expression was negatively correlated with down-regulation of hemoglobin and platelet counts. Consistent with a down-regulation of hemoglobin expression, peripheral RBC counts tended to increase during the acute malaria. In our model, up-regulations of RBC and/or leucocyte binding mediators like CD36, ICAM1, thrombospondin, and thrombomodulin may contribute to the pathogenesis of cerebral malaria. Similarly, up-regulation of genes coding for glycolytic enzymes, glucose transporter and H+-ATPases may contribute to the hypoglycemia and metabolic acidosis frequently observed in seriously ill malaria patients. Overall gender effects on gene expression profiles between male and female subjects were not apparent, except that some hemoglobins were significantly down-regulated in male versus female; suggesting males may be more prone to the development of malaria associate anemia.
Highlights
Malaria pathogenesis needs to be understood better
High serum TNF-α levels correlate with the development of cerebral malaria [23], this complication may be related to the increased adherence of RBCs or leukocytes to up-regulated integrins like CD36 and ICAM1, and may be related to coagulation proteins, like thrombospondin, being expressed on the surface of endothelial cells [2]
The results suggest that cerebral malaria may be associated with an upregulation of integrins, like CD36 and ICAM1, and coagulation factors, like thrombospondin and thrombomodulin, which may help set the stage for this very serious complication by increasing the adherence of RBCs and leucocytes to the vascular bed of the brain
Summary
Malaria pathogenesis needs to be understood better. Infection with P. falciparum malaria is generally associated with severe symptoms and complications, including high fever/chills and anemia. It has been postulated that the hypoglycemia and metabolic acidosis seen in some malaria patients may be due to a general up-regulation of host glycolysis after infection and that thrombocytopenia may be related to the destruction or decreased production of platelets during the acute stages of the disease [1]. In all cases, these models of malaria pathogenesis need further evaluation and development. Microarray analysis of gene expression profiles associated with the early, acute, and recovery stages of the malaria disease cycle may provide an excellent opportunity to further examine these events at the cellular and molecular level
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