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Disruption of CD36 Impairs Cytokine Response to Plasmodium falciparum Glycosylphosphatidylinositol and Confers Susceptibility to Severe and Fatal Malaria In Vivo¹

Samir N. Patel^*,, Ziyue Lu^*, Kodjo Ayi^*, Lena Serghides^*, D. Channe Gowda and Kevin C. Kain^2,*,,

^* McLaughlin-Rotman Centre, University Health Network-Toronto General Hospital, McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University Health Network-Toronto General Hospital, Toronto, Ontario, Canada

CD36 is a scavenger receptor that has been implicated in malaria pathogenesis as well as innate defense against blood-stage infection. Inflammatory responses to Plasmodium falciparum GPI (pfGPI) anchors are believed to play an important role in innate immune response to malaria. We investigated the role of CD36 in pfGPI-induced MAPK activation and proinflammatory cytokine secretion. Furthermore, we explored the role of this receptor in an experimental model of acute malaria in vivo. We demonstrate that ERK1/2, JNK, p38, and c-Jun became phosphorylated in pfGPI-stimulated macrophages. In contrast, pfGPI-induced phosphorylation of JNK, ERK1/2, and c-Jun was reduced in Cd36^–/– macrophages and Cd36^–/– macrophages secreted significantly less TNF- in response to pfGPI than their wild-type counterparts. In addition, we demonstrate a role for CD36 in innate immune response to malaria in vivo. Compared with wild-type mice, Cd36^–/– mice experienced more severe and fatal malaria when challenged with Plasmodium chabaudi chabaudi AS. Cd36^–/– mice displayed a combined defect in cytokine induction and parasite clearance with a dysregulated cytokine response to infection, earlier peak parasitemias, higher parasite densities, and higher mortality rates than wild-type mice. These results provide direct evidence that pfGPI induces TNF- secretion in a CD36-dependent manner and support a role for CD36 in modulating host cytokine response and innate control of acute blood-stage malaria infection in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Canadian Institutes of Health Research Team Grant in Malaria (to K.C.K.), Operating Grant MT-13721 (to K.C.K.), Genome Canada Ontario through the Ontario Genomics Institute (to K.C.K.), Canadian Genetics Disease Network (to K.C.K.), Physicians Services Inc. (to K.C.K.), and a Canadian Institutes of Health Research Canada Research Chair (to K.C.K.).

² Address correspondence and reprint requests to Dr. Kevin C. Kain, University Health Network-Toronto General Hospital, EN 13-214, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail address: kevin.kain{at}uhn.on.ca

³ Abbreviations used in this paper: PCCAS, Plasmodium chabaudi chabaudi AS; pfGPI, Plasmodium falciparum GPI; PEs, parasitized erythrocyte; M, monocyte/ macrophage.

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