title: Functional roles for C5a and C5aR but not C5L2 in the pathogenesis of human and experimental cerebral malaria.
abstract: The host immune response plays an important role in the onset and progression of cerebral malaria (CM). The complement system is an essential component of the innate immune response to malaria, and its activation generates the anaphylatoxin C5a. To test the hypothesis that C5a signaling contributes to the pathogenesis of CM, we investigated a causal role for the C5a receptors C5aR and C5L2 in a mouse model of experimental CM (ECM) induced by Plasmodium berghei ANKA infection, and using a case-control design, we examined levels of C5a in plasma samples from Ugandan children presenting with CM or uncomplicated malaria (UM). In the ECM model, C5aR(-/-) mice displayed significantly improved survival compared to their wild-type (WT) counterparts (P = 0.004), whereas C5L2(-/-) mice showed no difference in survival from WT mice. Improved survival in C5aR(-/-) mice was associated with reduced levels of the proinflammatory cytokines tumor necrosis factor (TNF) and gamma interferon (IFN-γ) and the chemokine, monocyte chemoattractant protein 1 (MCP-1) (CCL2). Furthermore, endothelial integrity was enhanced, as demonstrated by increased levels of angiopoietin-1, decreased levels of angiopoietin-2 and soluble ICAM-1, and decreased Evans blue extravasation into brain parenchyma. In the case-control study, the median levels of C5a at presentation were significantly higher in children with CM versus those in children with UM (43.7 versus 22.4 ng/ml; P < 0.001). These findings demonstrate that C5a is dysregulated in human CM and contributes to the pathogenesis of ECM via C5aR-dependent inflammation and endothelial dysfunction.
authors.affiliation: Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hani
authors.initials: H
authors.lastname: Kim
authors.forename: Laura K
authors.initials: LK
authors.lastname: Erdman
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Lu
authors.forename: Lena
authors.initials: L
authors.lastname: Serghides
authors.forename: Kathleen
authors.initials: K
authors.lastname: Zhong
authors.forename: Aggrey
authors.initials: A
authors.lastname: Dhabangi
authors.forename: Charles
authors.initials: C
authors.lastname: Musoke
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Christine
authors.initials: C
authors.lastname: Cserti-Gazdewich
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015936:Complement C5a / Q000172:deficiency / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000276:immunology*; D011951:Receptors, Complement / Q000172:deficiency / Q000276:immunology*; D011952:Receptors, Concanavalin A
chemical_list: C417003:C5aR2 protein, human; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D011952:Receptors, Concanavalin A; D015936:Complement C5a