Study Shows That SARS-CoV-2 Coronavirus Hijacks Human Host Metabolic Pathways For Its Replicative Advantage!

Researchers from the Karolinska Institute-Sweden, Södersjukhuset/The South General Hospital-Sweden, Stockholm University-Sweden, Indian Institute of Science (IISc)-India and Umeå University-Sweden have in a new study discovered that the SARS-CoV-2 coronavirus typically hijacks the human host metabolic pathways for its replicative advantage.


 
It has been known that viruses typically hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in COVID-19 disease severity in patients but lacked mechanistic insights.
 
Utilizing patient- derived multi-omics data and in vitro infection assays, the study team aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity.
 
The study findings suggest that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism.
 
The study team found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, the study findings highlight that the SARS-CoV-2 virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.
 
The study findings were published on a preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2021.02.24.432759v1
 
The study team comprising of scientists from Sweden and India characterized the host cell metabolic alterations associated with SARS-CoV-2 infection.
 
Their study findings reveal that SARS-CoV-2 modulates the host cell's central carbon metabolism to facilitate replication and infection propagation.
 
The team also observed that the severity of the COVID-19 disease primarily depends on the blood levels of glucose, mannose, and glutamate.
 
From ts emergence in late December 2019 in Wuhan, China, SARS-CoV-2, the causative pathogen of COVID-19 disease, has infected 114.3 million individuals and claimed 2.54 million lives globally.
 
Despite the fact that about 80% of COVID-19 patients remain asymptomatic or mildly symptomatic, the risk of developing severe disease is higher among individuals with metabolic comorbidities, such as diabetes and obesity.
 
Furthermore there is evidence showing that COVID-19 severity is associated with a n umber of metabolic alterations, including increased amino acid and fatty acid synthesis and altered lipid and energy metabolism.
 
Interestingly regarding viral life-cycle, it is known that glucose and glutamine as extracellular carbon sources are typically required for the viral replication and that a virus is capable of modulating a number of host cell metabolic pathways, including central carbon metabolism, of facilitating its life-cycle.
 
Studies have also shown that targeting glycolysis and PI3K/AKT signaling pathways by small molecule inhibitors can lead to a significant reduction in viral load in infected cells.
 
The study team explored the involvement of key host cell metabolic pathways in SARS-CoV-2 replication. They have also investigated whether alterations in host cell metabolic profiles are associated with COVID-19 severity.   
    
The study team analyzed 92 inflammatory mediators in plasma using a targeted proteomics approach. Moreover, they conducted plasma metabolic profiling using untargeted metabolomics, followed by lymphocyte and monocyte immune phenotyping towards metabolite transporters.
 
The team also in a separate set of in vitro experimentations, conducted quantitative untargeted proteomics using SARS-CoV-2-infected lung, liver, kidney, and colon cells to understand virus-mediated metabolic remodeling.
Important observations
 
The detailed proteomics and metabolomics analyses were conducted using plasma samples collected from hospitalized COVID-19 patients having either mild or severe form of the disease. The targeted proteomics data revealed significantly elevated cytokines and chemokines in both mild and severe COVID-19 patients. Interestingly, the scientists observed a reduced level of interleukin 12 (IL-12) in severe COVID-19 patients compared to that in mildly affected patients.
 
In all, a total of 444 significantly altered metabolites were identified in COVID-19 patients using untargeted plasma metabolomics.
 
Interestingly the majority of these metabolites were lipids and amino acids.
 
Upon further analysis, the study team noticed that amino acid metabolism pathways were primarily affected by SARS-CoV-2 infection. Interestingly, they observed that the levels of glycolysis and TCA cycle-associated metabolites varied significantly between COVID-19 patients with diverse disease severities.
 
Also while comparing mild and severe COVID-19 patients, the study team observed that various amino acid-related pathways, insulin signaling pathways, and macrophage-mediated IL-12 production and signaling were maximally affected in severe patients. They identified plasma levels of glucose, mannose, and glutamate as the major determinants of disease severity with further analysis.
 
Importantly although they observed an elevated plasma level of mannose-binding lectin in COVID-19 patients, there was no association between the mannose and mannose-binding lectin levels.
 
Considering that the metabolite transporters can regulate the functions of immune cells, such as lymphocytes and monocytes, by controlling nutrient supply, the scientists conducted immune phenotyping of glucose, mannose, and glutamate transporters.
 
The study team observed significantly reduced lymphocyte levels, mildly elevated intermediate monocyte levels, and noticeably decreased non-classical monocyte levels in COVID-19 patients. These observations indicate a significant involvement of monocytes in altered immune responses during SARS-CoV-2 infection. Interestingly, they observed significantly elevated expressions of metabolite transporters in all subpopulations of monocytes studied.
 
Importantly the in vitro experimentations conducted to evaluate acute host cell metabolic alterations in response to SARS-CoV-2 infection revealed that proteins associated with glycolysis/gluconeogenesis and fructose and mannose metabolism were significantly elevated in lung cells whereas mitochondrial TCA cycle proteins were significantly reduced. This indicates that SARS-CoV-2 infection might cause mitochondrial dysfunction.
 
Besides glucose and glutamate, the study team observed elevated pyruvate levels, lactate and α-ketoglutarate, indicating significant involvement of glycolysis and glutaminolysis pathways in SARS-CoV-2 infection. Given these findings, they blocked these pathways and observed a significant reduction in viral replication. By varying the amount of glucose and mannose in culture media containing SARS-CoV-2-infected cells, they observed that viral replication is affected by increased glucose levels.
 
The research findings indicate that to facilitate replication, the SARS-CoV-2 coronavirus modulates host cell central carbon metabolism, converting carbohydrates into precursors for metabolism.
 
Furthermore, the research identifies metabolites of the carbohydrate and amino acid metabolism pathways as potential biomarkers for predicting COVID-19 severity.
 
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