Plasma metabolomics and gene regulatory networks analysis reveal the role of nonstructural SARS-CoV-2 viral proteins in metabolic dysregulation in COVID-19 patients

Abstract

Metabolomic analysis of blood plasma samples from COVID-19 patients is a promising approach allowing for the evaluation of disease progression. We performed the metabolomic analysis of plasma samples of 30 COVID-19 patients and the 19 controls using the high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometric detection (LC-MS/MS). In our analysis, we identified 103 metabolites enriched in KEGG metabolic pathways such as amino acid metabolism and the biosynthesis of aminoacyl-tRNAs, which differed significantly between the COVID-19 patients and the controls. Using ANDSystem software, we performed the reconstruction of gene networks describing the potential genetic regulation of metabolic pathways perturbed in COVID-19 patients by SARS-CoV-2 proteins. The nonstructural proteins of SARS-CoV-2 (orf8 and nsp5) and structural protein E were involved in the greater number of regulatory pathways. The reconstructed gene networks suggest the hypotheses on the molecular mechanisms of virus-host interactions in COVID-19 pathology and provide a basis for the further experimental and computer studies of the regulation of metabolic pathways by SARS-CoV-2 proteins. Our metabolomic analysis suggests the need for nonstructural protein-based vaccines and the control strategy to reduce the disease progression of COVID-19.

Figure 1

Gene networks describing mitochondrial (A) and cytoplasmic (B) P₂ pathways, by which the virus, potentially, affects the proteins of aminoacyl-tRNA biosynthesis. The bigger balls show the proteins of aminoacyl-tRNA biosynthesis, while the smaller ones designate other proteins. The pathways discussed in the text are outlined.

Figure 2

Gene networks describing P₇ pathways, by which the virus, potentially, affects the proteins of aminoacyl-tRNA biosynthesis. The bigger balls show the proteins of aminoacyl-tRNA biosynthesis, while the smaller ones designate other proteins. Spirals designate the genes.

Figure 3

The scheme of glycine, serine and threonine metabolism extracted from KEGG database (https://www.kegg.jp/pathway/hsa00260). Enzymes that can be the potential targets of viral proteins are shown by red boxes, metabolites increased in the plasma of COVID-19 patients are underscored by red line, while those decreased are underscored by blue line.

Figure 4

Gene network describing P₅ pathways of gene expression regulation of glycine, serine and threonine metabolism. The bigger balls show the proteins of glycine, serine and threonine metabolism, while the smaller ones designate other proteins. Spirals designate the genes. The pathways discussed in the text are outlined.

Figure 5

The scheme of arginine biosynthesis extracted from KEGG database (Id hsa00220). Enzymes that can be the potential targets of viral proteins are shown by red boxes, the metabolites increased in the plasma of COVID-19 patients are underscored by red line, while those decreased are underscored by blue line.

Figure 6

Gene network describing P₄ and P₅ pathways of arginine biosynthesis gene expression regulation. The bigger balls show the arginine biosynthesis proteins, while the smaller ones designate other proteins. Spirals designate the genes.

Figure 7

Pathways of arginase 2 (ARG2) expression regulation by viral proteins. The bigger ball designates ARG2, while the smaller ones designate other proteins. Spirals designate the genes. The pathways discussed in the text are outlined.

Figure 8

Gene network describing P₃ and P₆ pathways regulating activity/stability of arginine biosynthesis enzymes by viral proteins. The bigger balls show the proteins of arginine biosynthesis, while the smaller ones designate other proteins. Spirals designate the genes. The pathways discussed in the text are outlined.

Figure 9

Gene network describing P₂ and P₇ pathways by which the viral proteins can influence the arginine biosynthesis proteins. The bigger balls show the proteins of arginine biosynthesis, while the smaller ones designate other proteins. Spirals designate the genes. The pathways discussed in the text are outlined.