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.

The altered molecular proteins and pathways in response to COVID-19 infection are still unclear. Here, we performed a comprehensive proteomics-based investigation of nasopharyngeal swab samples from COVID-19 patients to study the host response by employing simple extraction strategies. Few of the host proteins such as Interleukin-6, L-lactate dehydrogenase, C-reactive protein, Ferritin and Aspartate aminotransferase were found to be up-regulated only in COVID-19 positive patients using targeted Multiple Reaction Monitoring studies. The most important pathways identified by enrichment analysis were neutrophil degranulation, interleukin-12 signaling pathways and mRNA translation of proteins thus providing the detailed investigation of host response in COVID-19 infection. Thus, we conclude that mass spectrometry-detected host proteins have a potential for disease severity progression; however, suitable validation strategies should be deployed for the clinical translation. Furthermore, the in-silico docking of host proteins involved in the interleukin-12 signaling pathway might aid in COVID-19 therapeutic interventions.

The coronavirus disease 2019 (COVID-19) pandemic continues to ravage the world, with many hospitals overwhelmed by the large number of patients presenting during major outbreaks. A rapid triage for COVID-19 patient requiring hospitalization and intensive care is urgently needed. Age and comorbidities have been associated with a higher risk of severe COVID-19 but are not sufficient to triage patients. Here, we investigated the potential of attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy as a rapid blood test for classification of COVID-19 disease severity using a cohort of 160 COVID-19 patients. A simple plasma processing and ATR-FTIR data acquisition procedure was established using 75% ethanol for viral inactivation. Next, partial least-squares-discriminant analysis (PLS-DA) models were developed and tested using data from 130 and 30 patients, respectively. Addition of the ATR-FTIR spectra to the clinical parameters (age, sex, diabetes mellitus, and hypertension) increased the area under the ROC curve (C-statistics) for both the training and test data sets, from 69.3% (95% CI 59.8–78.9%) to 85.7% (78.6–92.8%) and 77.8% (61.3–94.4%) to 85.1% (71.3–98.8%), respectively. The independent test set achieved 69.2% specificity (42.4–87.3%) and 94.1% sensitivity (73.0–99.0%). Diabetes mellitus was the strongest predictor in the model, followed by FTIR regions 1020–1090 and 1588–1592 cm –1 . In summary, this study demonstrates the potential of ATR-FTIR spectroscopy as a rapid, low-cost COVID-19 severity triage tool to facilitate COVID-19 patient management during an outbreak.

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.

Background: COVID-19 severity is disproportionately high in the elderly and people with comorbidities. However, other factors that predispose individuals to increased chances of infection are unclear. Methods: Data from 18,600 people screened for COVID-19 in Mumbai during the outbreak's initial phase, March 7 to June 30, 2020, were used to assess risk factors associated with COVID-19 using the odds ratio analysis. Findings: Males aged 60 years having both diabetes and hypertension were at the highest risk of COVID-19 infection (M vs. F OR=2.5, 95% CI=1.34À4.67, p = 0.0049). People having both diabetes and hypertension in 20 years (OR=4.11, 95% CI=3.26À5.20, p <0.0001), diabetes and hypertension independently in 20À39 (OR=4.13, 95% CI=2.22À7.70, p <0.0001, OR=4.32, 95% CI=2.10À8.88, p = 0.0001) and 60 years (OR=2.69, 95% CI=1.87À3.87, p <0.0001, OR=2.03, 95% CI=1.46À2.82, p <0.0001), chronic renal disease in 20À39 years (OR=5.38, 95% CI=1.91À15.09, p = 0.0007) age groups had significantly higher risk of COVID-19 infection than those without comorbidity. Quarantined people had significantly lower positive odds (OR=0.59, 95% CI=0.53À0.66, p <0.001) than non-quarantined people. Interpretation: Our research indicates that the risk of getting COVID-19 disease is not equal. When considering sex, age, and comorbidity together, we found that males aged 60 years and having both diabetes and hypertension had a significantly high risk of COVID-19 infection. Therefore, remedial measures such as vaccination programs should be prioritized for at-risk individuals.