A Multi-omics Longitudinal Study Reveals Alteration of the Leukocyte Activation Pathway in COVID-19 Patients

Abstract

Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific molecular signatures associated with the elevated immune response are yet to be elucidated. We performed a mass-spectrometry-based proteomic and metabolomic analysis of COVID-19 plasma samples collected at two time points. Using Orbitrap Fusion LC–MS/MS-based label-free proteomic analysis, we identified around 10 significant proteins, 32 significant peptides, and 5 metabolites that were dysregulated at the severe time points. Few of these proteins identified by quantitative proteomics were validated using the multiple reaction monitoring (MRM) assay. Integrated pathway analysis using distinct proteomic and metabolomic signatures revealed alterations in complement and coagulation cascade, platelet aggregation, myeloid leukocyte activation pathway, and arginine metabolism. Further, we highlight the role of leukocyte activation and arginine metabolism in COVID-19 pathogenesis and targeting these pathways for COVID-19 therapeutics.

COVIDomics: The Proteomic and Metabolomic Signatures of COVID-19

“…A proteomic and metabolomic signature during the transition of COVID-19 severity was also established by Suvarna et al [ 76 ]. In particular, 5 metabolites (arginine, creatine, 3-hydroxyoctanoyl carnitine, 3,5-tetradecadiencarnitine, and 1-stearoyl-2-hydroxy-sn-glycero-3-PE) distinguished between severe and non-severe COVID-19, while 10 proteins resulted differential (HSPA8, IGFALS, LGALS3BP, PDIA3, PDLIM1, PFN1, PTGDS, RAP1B, SERPINA10, TGFB1).…”

“… The main findings obtained from the review of proteomics studies are summarized. In particular, the results from plasma [ 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ] and serum [ 43 , 44 , 45 , 46 , 47 , 83 , 86 ] studies were merged to identify the common proteins (top) that should represent the proteome signature of COVID-19. These protein entries were analyzed and clustered using STRING version 11.5, revealing the formation of three main clusters (bottom).…”

Immune Cell Plasticity in Inflammation: Insights into Description and Regulation of Immune Cell Phenotypes

“…The Stark/Massberg laboratory used an intriguing approach in assessing phenotypic configurations of immune cells in COVID-19 patients, revealing disturbed neutrophil and platelet activation patterns in the blood of COVID-19 patients, correlating with disease severity [ 12 ]. Additionally, other groups have shown, through various techniques, the tremendous impact COVID-19 has on leukocytes and platelets in particular, including IL-6-mediated platelet activation and STAT3 phosphorylation within monocytes and T cells [ 281 , 282 , 283 ]. As leukocyte and platelet dysregulated functionality is observable, the neutrophil activation marker CD177 can also be used for assessment of COVID-19 severity [ 174 ].…”

Application of omics technology to combat the COVID‐19 pandemic

“…223 In some other studies, arginine metabolism has also been found to be related to inflammatory cytokines and fatal outcomes in COVID‐19 patients. 224 , 225 Hypoxia caused by SARS‐CoV‐2 infection can inhibit the OXPHOS of mitochondria and led to a modified BCAA metabolism, which is closely related to the adverse clinical outcomes of severe COVID‐19 patients. 226 BCAAs administration was recommended as a strategy to maintain NAD balance in COVID‐19 critical patients.…”