Plasma proteomic signature predicts who will have persistent symptoms after SARS-CoV-2 infection

discussion

We report plasma proteomic responses to SARS-CoV-2 infection during the first wave in the UK, made possible by high-frequency serial biosampling of HCW at risk of infection during the peak of the first wave of the epidemic in London Non-severe SARS-CoV-2 infection markedly perturbs the plasma proteome from the time of first infection and during the following 6 weeks. This perturbation of plasma proteomics is related to the extent of symptoms and is associated with the presence of persistent symptoms (Figure 6).

Figure 6 Graphic summary.

The sustained perturbation of the plasma proteome after non-severe SARS-CoV-2 found in the current study fits with similar findings from a pilot using the same assay in SARS-CoV-2-infected individuals showing mild or absent symptoms .7

Doikov I
Hallqvist J
Gilmour KC
Grandjean L
Mills K
Heywood WE.

“The long tail of Covid-19” – The detection of a prolonged inflammatory response after SARS-CoV-2 infection in asymptomatic and mildly affected patients. PCA of the plasma proteome of this independent cohort was the most discriminating of infected cases (n = 10) compared to uninfected individuals (n = 10) at 6 weeks, consistent with our reported PCA findings in figure 2d. We go on to show that the plasma proteome of HCW in the week before PCR-confirmed SARS-CoV-2 infection is indistinguishable from that of uninfected HCW, that the earliest detectable perturbation coincides with the first positive PCR test result and which is progressively accentuated in the subsequent weeks, resulting in a complete separation of the groups from week five. A number of studies have previously undertaken a discovery proteomics approach to study the perturbation of the plasma proteome during acute infection,23.

Filbin Mr

Mehta A

Schneider AM

et al.

Longitudinal proteomic analysis of severe COVID-19 reveals signatures associated with survival, tissue-specific cell death, and cell-cell interactions.

Gisby J

Clarke CL

Medjeral-Thomas N

et al.

Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death.

Védula P

Tang HY

DW memory

Kashina A.

Post-translational signatures of proteins identified in the plasma of the COVID-19 patient.

Al-Nesf MAY

Abdesselem HB

Bensmail I

et al.

Prognostic tools and drug candidates based on plasma proteomics of patients with severe complications of COVID-19.

Saheb Sharif-Askari N

Saheb Sharif-Askari F

Madkhana B

et al.

Upregulation of oxidative stress gene markers during SARS-COV-2 viral infection.

Tong M

Jiang Y

Xia D

et al.

Elevated expression of serum endothelial cell adhesion molecules in patients with COVID-19. (eg NCAM2). However, the plasma proteome signatures of critically ill hospitalized patients are expected to be different from ours as a result of acute inflammatory changes that would occur not only from the initial infection but from the subsequent cascade of events that are not specific to COVID, such as mechanical ventilation or prolonged immobilization. . This can overshadow what may be subtle changes that occur due to the infection. A previous study that also looked at non-hospitalized SARS-CoV-2 patients found that certain symptoms such as fatigue and shortness of breath were still present up to 4–7 months after infection.30

Agustin M

swingers P

Stecher M

et al.

Post-COVID syndrome in non-hospitalized patients with COVID-19: a longitudinal prospective cohort study. Only a serologic analysis of antibodies was performed and the results suggested that lower baseline IgG was related to persistence of symptoms. We found no significant association between anti-S1 and anti-NP levels at baseline in those with persistent symptoms up to 12 months. In our trial, one of the proteins that most strongly predicts persistent symptoms is APP, which in serum can act as an anticoagulant. About 90% of soluble APP is thought to be derived from the secretion of activated platelets and acts as an inhibitor of coagulation factors IXa and Xia.31

of Uscio LV

He T

Katusic ZS.

Expression and processing of amyloid precursor protein in vascular endothelium.

Crispin A

Guo C

Chen C

et al.

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia. and also predicted persistent symptoms. It is plausible that HSCB is released into the blood as a consequence of mitochondrial disruption by the destruction of red blood cells mediated by COVID. Indeed, it has been widely demonstrated33 that COVID-19 and the destruction of immune cells. that acute infection with COVID-19 causes multiple subtypes of autoimmune hemolytic anemia (AIHA), starting approximately 7 days after infectious symptoms. Therefore, what we can capture here by MS are milder subclinical forms of AIHA in non-severe SARS-CoV-2 infection that nevertheless cause measurable protein abnormalities in plasma. Extracellular HSP90, another heat shock protein that is functionally diverse but essential for maintaining healthy cells, could be indicative of vascular stress as it has been shown to be released by smooth muscle cells vascular under oxidative stress. Serum HSP90 is then thought to act as an IL-834-stimulating cytokine

Chung SW

Lee JH

Choi KH

et al.

Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells.

Štorkánová H

Oreska S

Špiritović M

et al.

Plasma levels of Hsp90 in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study.

Gavin AL

Huang D

Huber C

et al.

PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic acid sensing.

Doikov I

Hallqvist J

Gilmour KC

Grandjean L

Mills K

Heywood WE.

“The long tail of Covid-19” – The detection of a prolonged inflammatory response after SARS-CoV-2 infection in asymptomatic and mildly affected patients.

Xu Y

Schnorrer P

Project A

et al.

IL-10 controls cystatin C synthesis and blood concentration in response to inflammation by regulating IFN regulatory factor 8 expression.

Zhao I

Qin L

Zhang P

et al.

Longitudinal profiling of COVID-19 associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. This corroborates what we observe for CST3, as mild infection has increased cystatin C that is not being suppressed by higher levels of IL-10. S100A9 is part of calprotectin, which is a marker of neutrophil-related inflammatory processes. Silvin et al. first described that elevated calprotectin may indicate abnormal myeloid cells leading to severe infection in patients infected with SARS-CoV-2. Since then, many studies have now determined calprotectin as a biomarker of severe SARS-CoV-2 infection.

Mahler M

Meroni PL

Infantino M

You are Buhler

Fritzler MJ.

Circulating calprotectin as a biomarker of the severity of COVID-19.,40 Plasma proteomics identifies biomarkers and pathogenesis of COVID-19. detectable in blood and lungs. Although the levels we observed were much lower than expected in severely affected patients, our data suggest that higher calprotectin levels in mildly symptomatic patients at the time of first infection could be a risk marker for persistent symptoms. Recent studies have shown that impaired lung function is detectable several months after infection with SARS-CoV-241

Townsend L

Dowds J

O’Brien K

et al.

Persistent ill health after COVID-19 is not associated with respiratory complications or baseline disease severity.

Cheon IS

Lee C

Son YM

et al.

Immune signatures underlying the post-acute pulmonary sequelae of COVID-19.

Vijayakumar B

Boustani K

Ogger PP

et al.

Immunoproteomic profiling reveals aberrant regulation of immune cells in the airways of individuals with ongoing post-COVID-19 respiratory disease.

Crispin A

Guo C

Chen C

et al.

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia. and have links to lung disease, so it is plausible that we are detecting surrogate indicators of possible mild impairment of lung function. Pathway enrichment analysis of samples from our healthcare workers with non-severe SARS-CoV-2 infection revealed previously reported pathways, including lipid atherosclerosis and cholesterol. metabolic pathways,28 Metabolic reprogramming in COVID-19.