Abstract
The pestilential pathogen SARS-CoV-2 has led to a seemingly ceaseless pandemic of COVID-19. The healthcare sector is under a tremendous burden, thus necessitating the prognosis of COVID-19 severity. This in-depth study of plasma proteome alteration provides insights into the host physiological response towards the infection and also reveals the potential prognostic markers of the disease. Using label-free quantitative proteomics, we performed deep plasma proteome analysis in a cohort of 71 patients (20 COVID-19 negative, 18 COVID-19 non-severe, and 33 severe) to understand the disease dynamics. Of the 1200 proteins detected in the patient plasma, 38 proteins were identified to be differentially expressed between non-severe and severe groups. The altered plasma proteome revealed significant dysregulation in the pathways related to peptidase activity, regulated exocytosis, blood coagulation, complement activation, leukocyte activation involved in immune response, and response to glucocorticoid biological processes in severe cases of SARS-CoV-2 infection. Furthermore, we employed supervised machine learning (ML) approaches using a linear support vector machine model to identify the classifiers of patients with non-severe and severe COVID-19. The model used a selected panel of 20 proteins and classified the samples based on the severity with a classification accuracy of 0.84. Putative biomarkers such as angiotensinogen and SERPING1 and ML-derived classifiers including the apolipoprotein B, SERPINA3, and fibrinogen gamma chain were validated by targeted mass spectrometry-based multiple reaction monitoring (MRM) assays. We also employed an in silico screening approach against the identified target proteins for the therapeutic management of COVID-19. We shortlisted two FDA-approved drugs, namely, selinexor and ponatinib, which showed the potential of being repurposed for COVID-19 therapeutics. Overall, this is the first most comprehensive plasma proteome investigation of COVID-19 patients from the Indian population, and provides a set of potential biomarkers for the disease severity progression and targets for therapeutic interventions.
Highlights
A previously unknown infectious virus has triggered a raging pandemic of COVID-19 in the year 2020
These results provide valuable information on plasma biomarkers associated with severity of COVID-19 and unravel the mechanistic pathways related to SARS-CoV-2 infection
We found that selinexor, an exportin antagonist, and ponatinib, a tyrosine kinase inhibitor, approved for use in treatment of multiple myeloma and chronic myeloid leukemia (CML), respectively, can be used to target proteins altered in severe cases as compared with non-severe
Summary
A previously unknown infectious virus has triggered a raging pandemic of COVID-19 in the year 2020. It has left behind a trail of more than a million dead and destroyed life and livelihood. SARS-CoV-2 attaches to the angiotensinconverting enzyme 2 (ACE2) and infects the respiratory tract and lungs, mostly leading to typical flu-like symptoms such as dry cough, body ache, and fever (Li et al, 2020). It can lead to acute respiratory distress syndrome Patients with such severe symptoms deteriorate leading to multiorgan dysfunction and eventually death (Huang et al, 2020; Zhou et al, 2020) despite intense medical intervention. SARS-CoV-2 primarily targets the respiratory tract and lung, several research studies have reported that the virus infects other organs like the gastrointestinal tract, liver, kidney, cardiac muscles, central nervous system, musculoskeletal system, and even reproductive system in males (Kimhofer et al, 2020; Nie et al, 2020)
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