Longitudinal Plasma Proteomics Analysis Reveals Novel Candidate Biomarkers in Acute COVID-19

Abstract

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose–bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

“…How proinflammatory cytokines disturb the vasculature is multifactorial, but these relationships suggest that some of the disruptive vascular effects may be mediated through cytokine induction of LRG1. Consistent with this possibility, circulating LRG1 levels have been reported to be raised in severe COVID-19 patients 38 – 41 and in patients with vasculitis 42 , 43 , where vascular damage is a primary feature.…”

“…Although blocking IL-6 signalling as a therapeutic intervention has been extensively studied in other diseases 53 , 54 , randomised controlled clinical trials with biologics targeting the IL-6 receptor, including Tocilizumab, have already shown some evidence of clinical benefit in COVID-19 cases 55 – 58 . Notably, COVID-19 patients have also been found to exhibit significantly enhanced circulating levels of LRG1 that, along with other biomarkers, can distinguish mild from severe disease 38 – 41 . These data raise the possibility that IL-6 induces systemic and local upregulation of LRG1 in COVID-19 patients that will then exert its angiopathic role on the pulmonary microvasculature.…”

Profiling the serum proteome during Schistosoma mansoni infection in the BALB/c mice: A focus on the altered lipid metabolism as a key modulator of host-parasite interactions

“…Their altered levels in the serum of infected animals is possibly a non-specific response to the antigenic burden associated with the parasitism. In agreement, a recent plasma proteome study with patients on acute phase COVID-19 ( 16 ) and on infants that had been exposed to Zika Virus ( 17 ), demonstrated a similar set of molecules exhibiting altered levels in the plasma associated with both infectious diseases.…”

Mapping the Serum Proteome of COVID-19 Patients; Guidance for Severity Assessment

“…Moreover, the observation frequency of the protein alterations across independent studies might be considered as a reference of its reliability and its association with COVID-19. Of the regulated protein panel, thirty-four proteins have been also reported in five or more studies, twenty-four in two to five, and four were reported only in one study from other authors [ 10 , 11 , 12 , 13 , 14 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]; specifically, CD14, CRP, ITIH1, ITIH3, LBP, LRG1, SERPINA3, VWF, C9, ApoA1 and GSN have been associated with COVID-19 severity in at least eight independent studies ( Supplementary Table S3 ).…”