Bone marrow chimeric mice reveal a dual role for CD36 in Plasmodium berghei ANKA infection

Abstract

Background: 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. 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.

Methods: Using 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.

Results: All 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.

Conclusion: The 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.

Figure 1

Bone marrow chimeric mice with CD36 expression confined to lethal radiation-sensitive cells are partially protected from CM. (A) Cumulative survival and parasitaemias (C) of CD36^+/+ into CD36^+/+ (n = 11) and CD36^-/- into CD36^+/+ (n = 11) through the course of P. berghei ANKA infection. (B) Cumulative survival and parasitaemias (D) of CD36^+/+ into CD36^-/- (n = 31) and CD36^-/- into CD36^-/- (n = 18) through the course of P. berghei ANKA infection. Survival curves represent the summary of four of independent experiments. Parasitaemia curves are from one representative experiment out of the four performed. In two independent experiments, CD36^+/+bm^CD36-/- and CD36^-/-bm^CD36+/+ were generated and infected at same time. LOG-RANK Test: P < .001 for curve (B). ● CD36^+/+ into CD36^+/+, ○ CD36^-/- into CD36^+/+, ◆ CD36^-/- into CD36^-/-, ◇ CD36+/+ into CD36^-/-. Gray area represents the time window for ECM development.