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S1P is associated with protection in human and experimental cerebral malaria

S1P is associated with protection in human and experimental cerebral malaria
S1P is associated with protection in human and experimental cerebral malaria
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 IFN? 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.

1076-1551
717-725
Finney, C.A.
fe9af9be-e26f-42d1-8918-b4911587d389
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Kain, A.
51f22546-832f-4844-bb0c-aea8bc9cbd9f
Dhabangi, C.
73ad0f4e-71e3-4aa0-9fe8-2e8cf3d7b989
Musoke, C.
c346316c-fa88-47d8-94b4-ecbeee1c995f
Cserti-Gazdewich, C.
089e4e58-20e1-4426-94bc-057606231b97
Oravecz, T.
c71327fa-c2a0-4ea2-8ddf-14280dbff8cb
Liles, W.C.
d5797fd1-5212-42aa-8b63-5cc09d0e9ee5
Kain, K.C.
976160a5-efe3-4014-bcc0-3fbe9a569acc
Finney, C.A.
fe9af9be-e26f-42d1-8918-b4911587d389
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Kain, A.
51f22546-832f-4844-bb0c-aea8bc9cbd9f
Dhabangi, C.
73ad0f4e-71e3-4aa0-9fe8-2e8cf3d7b989
Musoke, C.
c346316c-fa88-47d8-94b4-ecbeee1c995f
Cserti-Gazdewich, C.
089e4e58-20e1-4426-94bc-057606231b97
Oravecz, T.
c71327fa-c2a0-4ea2-8ddf-14280dbff8cb
Liles, W.C.
d5797fd1-5212-42aa-8b63-5cc09d0e9ee5
Kain, K.C.
976160a5-efe3-4014-bcc0-3fbe9a569acc

Finney, C.A., Hawkes, C.A., Kain, A., Dhabangi, C., Musoke, C., Cserti-Gazdewich, C., Oravecz, T., Liles, W.C. and Kain, K.C. (2011) S1P is associated with protection in human and experimental cerebral malaria. Molecular Medicine, 17 (7-8), 717-725. (doi:10.2119/molmed.2010.00214).

Record type: Article

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 IFN? 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.

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Published date: 2011
Organisations: Faculty of Medicine

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Local EPrints ID: 353198
URI: http://eprints.soton.ac.uk/id/eprint/353198
ISSN: 1076-1551
PURE UUID: 1db3c80e-af6f-4fcc-bb00-2a4474b5a3ea

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Date deposited: 03 Jun 2013 12:27
Last modified: 16 Jul 2019 21:32

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Contributors

Author: C.A. Finney
Author: C.A. Hawkes
Author: A. Kain
Author: C. Dhabangi
Author: C. Musoke
Author: C. Cserti-Gazdewich
Author: T. Oravecz
Author: W.C. Liles
Author: K.C. Kain

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