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.

A considerable section of males suffered from COVID-19, with many experiencing long-term repercussions. Recovered males have been documented to have compromised fertility, albeit the mechanisms remain unclear. We investigated the impact of COVID-19 on semen proteome following complete clinical recovery using mass spectrometry. A label-free quantitative proteomics study involved 10 healthy fertile subjects and 17 COVID-19-recovered men. With 1% false discovery rate and >1 unique peptide stringency, MaxQuant analysis found 1099 proteins and 8503 peptides. Of the 48 differentially expressed proteins between the healthy and COVID-19-recovered groups, 21 proteins were downregulated and 27 were upregulated in COVID-19-recovered males. The major pathways involved in reproductive functions, such as sperm–oocyte recognition, testosterone response, cell motility regulation, adhesion regulation, extracellular matrix adhesion, and endopeptidase activity, were downregulated in COVID-19-recovered patients according to bioinformatics analysis. Furthermore, the targeted approach revealed significant downregulation of semenogelin 1 and prosaposin, two proteins related to male fertility. Therefore, we demonstrate the alteration of semen proteome in response to COVID-19, thus disrupting the male reproductive function despite the patient’s clinical remission. Hence, to understand fertility-related biological processes triggered by this infection, a protracted evaluation of the consequences of COVID-19 in recovered men is warranted.