Abstract
BackgroundPlasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.MethodsPostmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.ResultsAfter Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.ConclusionThe parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.
Highlights
Plasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality
Recent studies have shown that mechanical blockage caused by sequestration of parasitized red blood cells, leukocytes and platelets [3,4,8,9,10,11,12], secretion of cytokines and chemokines [2,6,7,13], angiogenic failure [14,15], immune status and the genetic background of the host, and parasite factors [7,16] are involved in the pathogenesis of CM
We investigated the serum and cerebrospinal fluid (CSF) profiles of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GMCSF, IFN-γ, tumor necrosis factor (TNF)-α, inducible protein 10 (IP-10), monocyte chemotactic protein (MCP)-1 (MCAF), macrophage inflammatory protein (MIP)-1α, MIP1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP9, TGF-β1, Platelet derived growth factor (PDGF) bb and Vascular endothelial growth factor (VEGF)) in order to identify the immune factors which influence progression to fatal outcomes associated with CM
Summary
Plasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. It is generally accepted that two major factors are involved: (i) metabolic insufficiencies due to the sequestration of pRBCs, leukocytes and platelets within brain vessels via upregulated adhesion molecules [3,4,8,9,10,11,12], and (ii) immunological reactions with the local involvement of T cells and monocytes activated by Plasmodium antigens [7,11] These two major mechanisms appear to act together under the control of cytokines [7], and chemokines [2] to exacerbate CM
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