Ebola virus-like particles reprogram cellular metabolism

Abstract

Ebola virus can trigger a release of pro-inflammatory cytokines with subsequent vascular leakage and impairment of clotting finally leading to multiorgan failure and shock after entering and infecting patients. Ebola virus is known to directly target endothelial cells and macrophages, even without infecting them, through direct interactions with viral proteins. These interactions affect cellular mechanics and immune processes, which are tightly linked to other key cellular functions such as metabolism. However, research regarding metabolic activity of these cells upon viral exposure remains limited, hampering our understanding of its pathophysiology and progression. Therefore, in the present study, an untargeted cellular metabolomic approach was performed to investigate the metabolic alterations of primary human endothelial cells and M1 and M2 macrophages upon exposure to Ebola virus-like particles (VLP). The results show that Ebola VLP led to metabolic changes among endothelial, M1, and M2 cells. Differential metabolite abundance and perturbed signaling pathway analysis further identified specific metabolic features, mainly in fatty acid-, steroid-, and amino acid-related metabolism pathways for all the three cell types, in a host cell specific manner. Taken together, this work characterized for the first time the metabolic alternations of endothelial cells and two primary human macrophage subtypes after Ebola VLP exposure, and identified the potential metabolites and pathways differentially affected, highlighting the important role of those host cells in disease development and progression. KEY MESSAGES: • Ebola VLP can lead to metabolic alternations in endothelial cells and M1 and M2 macrophages. • Differential abundance of metabolites, mainly including fatty acids and sterol lipids, was observed after Ebola VLP exposure. • Multiple fatty acid-, steroid-, and amino acid-related metabolism pathways were observed perturbed.

Keywords: Cellular metabolism; Ebola; Endothelial cells; Macrophage polarization.

Fig. 1

Principal component analysis and partial least squares discriminant analysis of ECs, M1, and M2 after treatment with/without Ebola VLP. The differences in the metabolic profiles between Ebola VLP treated vs. untreated ECs, M1, and M2 are shown in PCA (a–c) and PLS-DA (d–f), respectively. In both PCA and PLS-DA, red triangles represent cells cultured in the presence of Ebola VLP; blue circles are cells cultured without. Each triangle/circle corresponds to a sample

Fig. 2

Heatmap of respective significant peaks found in ECs, M1, and M2 after treatment with Ebola VLP in comparison with untreated. Heatmap visualizing the intensity of each significant peak measured in ECs (a), M1 (b), and M2 (c). The color scales between dark blue and bright yellow represent lower intensity to higher intensity, respectively

Fig. 3

Distribution of lipid classes across ECs, M1, and M2 after treatment with Ebola VLP compared to control. The distributions of several lipid classes, namely, FA, CAR, GPL, ST, and GL for treated cells compared to their control, are shown in (a) and (b), respectively. GL was detectable in M2 only. The number of peaks matched in the database was counted; each hit corresponds to one peak encountered once. All peaks were filtered to abbreviation: CAR, acylcarnitine; FA, fatty acids; GL, glycerolipids; GPL, glycerophospholipids; ST, sterol lipids