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. 2023 Nov 22;8(22):e172845.
doi: 10.1172/jci.insight.172845.

Endothelial transcriptomic analysis identifies biomarkers of severe and cerebral malaria

Cláudia Gomes  1 , Rosauro Varo  2   3 , Miquel Duran-Frigola  4 , Antonio Sitoe  3 , Rubão Bila  3 , Sonia Machevo  3 , Alfredo Mayor  2   3   5   6 , Quique Bassat  2   3   5   7   8 , Ana Rodriguez  1
Affiliations

Endothelial transcriptomic analysis identifies biomarkers of severe and cerebral malaria

Cláudia Gomes et al. JCI Insight. .

Abstract

Malaria can quickly progress from an uncomplicated infection into a life-threatening severe disease. However, the unspecificity of early symptoms often makes it difficult to identify patients at high risk of developing severe disease. Additionally, one of the most feared malaria complications - cerebral malaria - is challenging to diagnose, often resulting in treatment delays that can lead to adverse outcomes. To identify candidate biomarkers for the prognosis and/or diagnosis of severe and cerebral malaria, we have analyzed the transcriptomic response of human brain microvascular endothelial cells to erythrocytes infected with Plasmodium falciparum. Candidates were validated in plasma samples from a cohort of pediatric patients with malaria from Mozambique, resulting in the identification of several markers with capacity to distinguish uncomplicated from severe malaria, the most potent being the metallopeptidase ADAMTS18. Two other biomarkers, Angiopoietin-like-4 and Inhibin-βE were able to differentiate children with cerebral malaria within the severe malaria group, showing increased sensitivity after combination in a biomarker signature. The validation of the predicted candidate biomarkers in plasma of children with severe and cerebral malaria underscores the power of this transcriptomic approach and indicates that a specific endothelial response to P. falciparum-infected erythrocytes is linked to the pathophysiology of severe malaria.

Keywords: Endothelial cells; Infectious disease; Malaria.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists

Figures

Figure 1
Figure 1. Summary of study design and results.
Figure 2
Figure 2. Secretion of Angiopoietin-2 is induced by TNF but not by P. falciparum–iRBCL in HBMEC.
HBMEC were incubated with iRBCL at different concentrations (expressed as number of iRBC per cm2), RBCL (8 × 106/cm2), or TNF at the indicated ng/mL concentrations for 24 hours before collection of the culture media and determination of the levels of angiopoietin-2 by ELISA. Results represent the mean of duplicates of 3 independent experiments with SD. Statistical significance was determined by 1-way ANOVA with Dunnett’s multiple-comparison test (****P < 0.0001).
Figure 3
Figure 3. Candidate biomarker proteins secreted in response to P. falciparum but not in response to TNF.
HBMEC were incubated for the indicated time points with media (black line), TNF (1 μg/mL; gray line), RBCL (8 × 106 RBC/cm2; pink line), or P. falciparum–iRBCL (8 × 106 iRBC/cm2; purple line). The medium of independent duplicates for each condition was collected at each time point. Levels of candidate biomarker proteins were determined by ELISA. Graphs show the average of the duplicated determinations for each time point.
Figure 4
Figure 4. Candidate biomarkers validated in plasma samples.
Comparison between the levels of the candidate biomarkers in samples from randomly selected patients with UM (n = 17) and all available patients with CM (n = 23) by ELISA. Mean level (red line). Statistical significance was determined by Mann-Whitney U test (**P < 0.01; ****P < 0.0001).
Figure 5
Figure 5. Expression levels of 3 candidate biomarkers are significantly different in UM and SM groups.
Levels of the indicated biomarkers were determined in the plasma of children with UM (n = 128) or SM (n = 136) malaria by ELISA. Mean level (red line). Statistical significance was determined by Mann-Whitney U test (***P < 0.001; ****P < 0.0001). AUC with 95% CI and P value are shown.
Figure 6
Figure 6. Expression levels of 2 candidate biomarkers are significantly different in SM (noncerebral) and CM groups.
Levels of the indicated biomarkers were determined in the plasma of children with severe noncerebral (SM; n =113) or cerebral (CM; n = 23) malaria by ELISA. Mean level (red line). Relative units (RU) were calculated for each determination dividing by the average value of the control (SM) group. The highest of ANGPTL4 and INHBE values expressed in RU were selected and compared between SM and CM groups. Statistical significance was determined by Mann-Whitney U test (**P < 0.01; ****P < 0.0001). AUC with 95% CI and P value are shown.
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