title: S1P is associated with protection in human and experimental cerebral malaria.
abstract: Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL)(-/-) mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4(+) and CD8(+) T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.
authors.affiliation: SA Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, University Health Network and University of Toronto, Canada Faculty of Medicine, University of Toronto, Canada.
authors.forename: Constance Am
authors.initials: CA
authors.lastname: Finney
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Kain
authors.forename: Aggrey
authors.initials: A
authors.lastname: Dhabangi
authors.forename: Charles
authors.initials: C
authors.lastname: Musoke
authors.forename: Christine
authors.initials: C
authors.lastname: Cserti-Gazdewich
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007223:Infant; D007371:Interferon-gamma / Q000097:blood; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010091:Oximes / Q000494:pharmacology; D010962:Plasmodium berghei / Q000187:drug effects / Q000254:growth & development*; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C555223:1-(4-(1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime; D000962:Antimalarials; D037621:Artemisinins; D015815:Cell Adhesion Molecules; D007093:Imidazoles; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D010091:Oximes; D011409:Propylene Glycols; C060506:sphingosine 1-phosphate; D000077332:Artesunate; D007371:Interferon-gamma; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D000068876:Fingolimod Hydrochloride; D013110:Sphingosine