Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo.
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-alpha 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-alpha 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.
Patel
Samir N
SN
McLaughlin-Rotman Centre, University Health Network-Toronto General Hospital, McLaughlin Centre for Molecular Medicine, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, Canada.
Lu
Ziyue
Z
Ayi
Kodjo
K
Serghides
Lena
L
Gowda
D Channe
DC
Kain
Kevin C
KC
D000208:Acute Disease; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D017261:Glycosylphosphatidylinositols / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D018512:Parasitemia / Q000235:genetics / Q000276:immunology; D016788:Plasmodium chabaudi / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha
D018955:CD36 Antigens; D017261:Glycosylphosphatidylinositols; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases