Abstract
BackgroundAdhesion of Plasmodium-infected red blood cells (iRBC) to different host cells, ranging from endothelial to red blood cells, is associated to malaria pathology. In vitro studies have shown the relevance of CD36 for adhesion phenotypes of Plasmodium falciparum iRBC such as sequestration, platelet mediated clumping and non-opsonic uptake of iRBC. Different adhesion phenotypes involve different host cells and are associated with different pathological outcomes of disease. Studies with different human populations with CD36 polymorphisms failed to attribute a clear role to CD36 expression in human malaria. Up to the present, no in vivo model has been available to study the relevance of different CD36 adhesion phenotypes to the pathological course of Plasmodium infection.MethodsUsing CD36-deficient mice and their control littermates, CD36 bone marrow chimeric mice, expressing CD36 exclusively in haematopoietic cells or in non-haematopoietic cells, were generated. Irradiated CD36-/- and wild type mice were also reconstituted with syngeneic cells to control for the effects of irradiation. The reconstituted mice were infected with Plasmodium berghei ANKA and analysed for the development of blood parasitaemia and neurological symptoms.ResultsAll mice reconstituted with syngeneic bone marrow cells as well as chimeric mice expressing CD36 exclusively in non-haematopoietic cells died from experimental cerebral malaria between day 6 and 12 after infection. A significant proportion of chimeric mice expressing CD36 only in haematopoietic cells did not die from cerebral malaria.ConclusionThe analysis of bone marrow chimeric mice reveals a dual role of CD36 in P. berghei ANKA infection. Expression of CD36 in haematopoietic cells, most likely macrophages and dendritic cells, has a beneficial effect that is masked in normal mice by adverse effects of CD36 expression in non-haematopoietic cells, most likely endothelial cells.
Highlights
Adhesion of Plasmodium-infected red blood cells to different host cells, ranging from endothelial to red blood cells, is associated to malaria pathology
Adhesion phenotypes involving CD36 include infected red blood cells (iRBC) binding to endothelial cells [13,14] and platelet mediated clumping [15], both of which contribute to the occlusion of the microvasculature in target organs
Since rodent malaria iRBCs bind CD36 [24,25], mouse models may be used to study the requirement of CD36 in various features of Plasmodium infection [26]
Summary
Adhesion of Plasmodium-infected red blood cells (iRBC) to different host cells, ranging from endothelial to red blood cells, is associated to malaria pathology. In vitro studies have shown the relevance of CD36 for adhesion phenotypes of Plasmodium falciparum iRBC such as sequestration, platelet mediated clumping and non-opsonic uptake of iRBC. Different adhesion phenotypes involve different host cells and are associated with different pathological outcomes of disease. The interactions of infected red blood cells (iRBC) with various cells of the host (often referred to as adhesion phenotypes) are thought to be involved in several features of the disease. Adhesion phenotypes involving CD36 include iRBC binding to endothelial cells [13,14] and platelet mediated clumping [15], both of which contribute to the occlusion of the microvasculature in target organs. The role of CD36 in the pathology of human malaria remains elusive and CD36-mediated adhesion cannot be considered as a validated target for anti-malarial intervention
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