Proteomic and Metabolomic Investigation of COVID-19 Patients with Elevated Serum Lactate Dehydrogenase

Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular mechanisms underneath remain poorly understood. In this study, 144 COVID-19 patients were enrolled to monitor the clinical and laboratory parameters over three weeks. Serum lactate dehydrogenase (LDH) was shown elevated in the COVID-19 patients on admission and declined throughout disease course, and its ability to classify patient severity outperformed other biochemical indicators. A threshold of 247 U/L serum LDH on admission was determined for severity prognosis. Next, we classified a subset of 14 patients into high- and low-risk groups based on serum LDH expression and compared their quantitative serum proteomic and metabolomic differences. The results found COVID-19 patients with high serum LDH exhibited differentially expressed blood coagulation and immune responses including acute inflammatory responses, platelet degranulation, complement cascade, as well as multiple different metabolic responses including lipid metabolism, protein ubiquitination and pyruvate fermentation. Specifically, activation of hypoxia responses was highlighted in patients with high LDH expressions. Taken together, our data showed that serum LDH levels are associated COVID-19 severity, and that elevated serum LDH might be consequences of hypoxia and tissue injuries induced by inflammation.

Multi-organ Proteomic Landscape of COVID-19 Autopsies

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. HIGHLIGHTSO_LICharacterization of 5336 regulated proteins out of 11,394 quantified proteins in the lung, spleen, liver, kidney, heart, thyroid and testis autopsies from 19 patients died from COVID-19. C_LIO_LICTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. C_LIO_LIEvidence for suppression of glucose metabolism in the spleen, liver and kidney; suppression of fatty acid metabolism in the kidney; enhanced fatty acid metabolism in the lung, spleen, liver, heart and thyroid from COVID-19 patients; enhanced protein translation initiation in the lung, liver, renal medulla and thyroid. C_LIO_LITentative model for multi-organ injuries in patients died from COVID-19: SARS-CoV-2 infection triggers hyperinflammatory which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart, kidney and thyroid. C_LIO_LITesticular injuries in COVID-19 patients included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. C_LI

Proteomics Uncovers Immunosuppression in COVID-19 Patients with Long Disease Course

Little is known regarding why a subset of COVID-19 patients exhibited prolonged positivity of SARS-CoV-2 infection. Here, we present a longitudinal sera proteomic resource for 37 COVID-19 patients over nine weeks, in which 2700 proteins were quantified with high quality. Remarkably, we found that during the first three weeks since disease onset, while clinical symptoms and outcome were indistinguishable, patients with prolonged disease course displayed characteristic immunological responses including enhanced Natural Killer (NK) cell-mediated innate immunity and regulatory T cell-mediated immunosuppression. We further showed that it is possible to predict the length of disease course using machine learning based on blood protein levels during the first three weeks. Validation in an independent cohort achieved an accuracy of 82%. In summary, this study presents a rich serum proteomic resource to understand host responses in COVID-19 patients and identifies characteristic Treg-mediated immunosuppression in LC patients, nominating new therapeutic target and diagnosis strategy.

Proteomic and Metabolomic Characterization of COVID-19 Patient Sera

Severe COVID-19 patients account for most of the mortality of this disease. Early detection and effective treatment of severe patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model correctly classified severe patients with an accuracy of 93.5%, and was further validated using ten independent patients, seven of which were correctly classified. We identified molecular changes in the sera of COVID-19 patients implicating dysregulation of macrophage, platelet degranulation and complement system pathways, and massive metabolic suppression. This study shows that it is possible to predict progression to severe COVID-19 disease using serum protein and metabolite biomarkers. Our data also uncovered molecular pathophysiology of COVID-19 with potential for developing anti-viral therapies.