Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection

Abstract

The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multiplatform metabolic phenotyping with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–mass spectrometry (LC-MS). Quantitative measurements of lipoprotein subfractions, α-1-acid glycoprotein, glucose, and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested positive for the SARS-CoV-2 virus ( n = 17) and from age- and gender-matched controls ( n = 25). Data were analyzed using an orthogonal-projections to latent structures (OPLS) method and used to construct an exceptionally strong (AUROC = 1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochemical relationships. Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer’s ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study reference: MTBLS2014.

NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines

“… 6 We have shown that SARS-CoV-2 infection induces a metabolic “phenoconversion” process that gives a characteristic complex blood plasma signature exhibiting multiple pathological effects of the disease and in a complex mosaic of biochemical change. 7 This COVID-19 phenoconversion signature is readily detectable by both nuclear magnetic resonance (NMR) and mass spectrometric techniques, with the spectral profiles providing multiple windows onto the disease sequelae in different organ systems. 7 The general term, phenoconversion, is defined here as follows: “The systemic shift in multiple molecular phenotypic properties from the healthy to a characteristic activated or pathophysiological state in response to an infectious or a pathophysiological challenge”.…”

“… 7 This COVID-19 phenoconversion signature is readily detectable by both nuclear magnetic resonance (NMR) and mass spectrometric techniques, with the spectral profiles providing multiple windows onto the disease sequelae in different organ systems. 7 The general term, phenoconversion, is defined here as follows: “The systemic shift in multiple molecular phenotypic properties from the healthy to a characteristic activated or pathophysiological state in response to an infectious or a pathophysiological challenge”. The term has previously been used to describe accurately, but more narrowly, the process of cellular metabolic activation by drugs to alter the biochemical response to subsequent drug treatments via enzyme induction.…”

“…We have suggested previously that the use of orthogonal phenoconversion tests for COVID-19 detection might be considered to augment polymerase chain reaction (PCR)-based diagnostics based on systemic disease effects. 7 Such diagnostics can also be extended to clinical trial monitoring 9 , 10 and long-term disease recovery studies. There are numerous possible spectroscopic approaches to such augmented COVID-19 diagnostics including NMR spectroscopy 7 , 11 and mass spectrometry, 12 , 13 and all these carry different and complementary information sets describing a particular condition.…”

“… 7 Such diagnostics can also be extended to clinical trial monitoring 9 , 10 and long-term disease recovery studies. There are numerous possible spectroscopic approaches to such augmented COVID-19 diagnostics including NMR spectroscopy 7 , 11 and mass spectrometry, 12 , 13 and all these carry different and complementary information sets describing a particular condition. Multiple studies have shown the potential of metabolic phenotyping with respect to the diagnosis of SARS-CoV-2 infection, and a comparison with healthy controls has indicated a distinctive pattern of underlying pathologies.…”

COVID-19 plasma deep proteome reveals distinct signatures in severe patients

“…However, although SARS-CoV-2 primarily targets the respiratory tract and lung, an increasing body of work has shown the virus to infect other organs like the gastrointestinal tract, liver, kidney, cardiac muscles, central nervous system, musculoskeletal system, and even reproductive system in males. 6,7 The diagnosis of the disease has been accurate and widespread. This was possible due to increased availability and deployment of RT-PCR assays, 8 or serological test kits, and scaling up of testing rates globally.…”