S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney, Constance A. M.; Hawkes, Cheryl A.; Kain, Dylan; Dhabangi, Aggrey; Musoke, Charles; Cserti‐Gazdewich, Christine; Oravecz, Tamás; Liles, W. Conrad; Kain, Kevin C.

doi:10.2119/molmed.2010.00214

Cited by 66 publications

(82 citation statements)

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“…In addition, our observations of endothelial activation and dysfunction following P. berghei ANKA infection are in agreement with accumulating evidence that increased levels of sICAM-1 and Ang-2, and decreased levels of Ang-1 are associated with both adverse clinical outcomes in human malaria infections and progression of ECM in mice (5,34,(45)(46)(47)(48)53). Of note, in the same cohort of Ugandan children with CM we studied with increased C5a levels, we also observed significantly increased levels of sICAM-1 and Ang-2 compared to those in children with uncomplicated malaria (34).…”

Section: Discussionsupporting

confidence: 91%

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Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria

Kim

Erdman

et al. 2014

Infect Immun

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fThe 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-␥) 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.

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Section: Discussionsupporting

confidence: 91%

“…Similar observations have been reported in ECM after P. berghei ANKA challenge (47,48). Consistent with these studies, we observed that P. berghei ANKA infection was associated with decreased levels of Ang-1 and increased levels of sICAM-1 in all three groups (Fig.…”

Section: Deletion Of C5ar But Not C5l2 Improves Survival In a Mouse Msupporting

confidence: 92%

Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria

Kim

Erdman

et al. 2014

Infect Immun

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“…Four studies determined the Ang-1 and/or the Ang-2 level in humans after start of anti-malarial treatment [29, 34, 36, 37]. Three studies investigated the effect of adjuvant therapy next to standard treatment on survival and on Ang-1 and/or Ang-2 levels in mice [38–40], two in humans [41, 42] and one in both humans and mice [26] during Plasmodium species infection (see Additional file 6). One study used a mouse model with one deleted Ang-1 allele [26] (see Additional file 6).…”

Section: Resultsmentioning

confidence: 99%

Systematic review of the role of angiopoietin-1 and angiopoietin-2 in Plasmodium species infections: biomarkers or therapeutic targets?

Jong

Slager

Verbon

et al. 2016

Malar J

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BackgroundLevels of both angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) correlate with malaria disease severity and are proposed as biomarkers and possible therapeutic targets. To establish their role in malaria, a systematic review was performed of the literature on Ang-1 and Ang-2 with regard to their potential as biomarkers in malaria and discuss their possible place in adjuvant treatment regimens.MethodsTen electronic databases were systematically searched to identify studies investigating Ang-1 and Ang-2 in human and murine malaria in both clinical and experimental settings. Information about the predictive value of Ang-1 and Ang-2 for disease severity and their regulatory changes in interventional studies were extracted.ResultsSome 579 studies were screened; 26 were included for analysis. In all five studies that determined Ang-1 levels and in all 11 studies that determined Ang-2 in different disease severity states in falciparum malaria, a decline in Ang-1 and an increase of Ang-2 levels was associated with increasing disease severity. All nine studies that determined angiopoietin levels in Plasmodium falciparum patients to study their ability as biomarkers could distinguish between multiple disease severity states; the more the disease severity states differed, the better they could be distinguished. Five studies differentiating malaria survivors from non-survivors with Ang-2 as marker found an AUROC in a range of 0.71–0.83, which performed as well or better than lactate. Prophylactic administration of FTY720, rosiglitazone or inhalation of nitric oxide (NO) during malaria disease in mice resulted in an increase in Ang-1, a decrease in Ang-2 and an increased survival. For rosiglitazone, a decrease in Ang-2/Ang-1 ratio was observed after post-infection treatment in mice and humans with malaria, but for inhalation of NO, an effect on Ang-1 and survival was only observed in mice.ConclusionBoth Ang-1 and Ang-2 levels correlate with and can distinguish between malaria disease severity states within the group of malaria-infected patients. However, distinct comparisons of disease severity states were made in distinct studies and not all distinctions made had clinical relevance. Changes in levels of Ang-1 and Ang-2 might also reflect treatment effectiveness and are promising therapeutic targets as part of multi-targeted therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1624-8) contains supplementary material, which is available to authorized users.

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“…Areas that require further study (“?”) include the role of PARs in CM and the extent to which ARs on ECs and DCs are critical in the DF-induced protective response against CM. Paradoxically, S1P receptors are implicated in the coagulation-inflammation cycle, 15 yet availability of S1P is important for protection against CM; 31 , therefore, the interactions between ARs, PARs, and S1P receptors, both in pathogenesis and in the context of DF treatment, should be investigated.…”

Section: Figurementioning

confidence: 99%