SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

Bharadwaj, Shiv; Singh, Mahendra; Kirtipal, Nikhil; Kang, Sang Gu

doi:10.3389/fmolb.2020.627842

Cited by 44 publications

(34 citation statements)

References 135 publications

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“…Prophylactic glutamine supplementation is recommended to those in high-risk groups; however, glutamine supplementation after the infection should be carefully considered. Glutamine supplementation may favor SARS-CoV-2 proliferation [ 121 ], although metabolomic analyses revealed that glutamine levels are relatively low [ 8 – 12 ]. In addition, small clinical trials showed that glutamine reduced the severity after infection in standard risk COVID-19 patients [ 122 , 123 ]; however, these preliminary findings need to be expanded to confidently assess glutamine supplementation in treating COVID-19.…”

Section: Drugs Targeting Hyaluronanmentioning

confidence: 99%

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Matsuyama

Yoshinaga²,

Shibue

et al. 2021

Cell Death Differ

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SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD + , coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3 + Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.

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Section: Drugs Targeting Hyaluronanmentioning

confidence: 99%

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Matsuyama

Yoshinaga²,

Shibue

et al. 2021

Cell Death Differ

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“…More importantly, we observed that the infection actively changes both metabolic and proteomic profile. Proteomic analysis of primary astrocytes in vitro, as well as dissected cortex and hippocampus in vivo, demonstrated relevant changes in proteins related to carbon metabolism, biosynthesis of amino acids and the The fact that viruses actively hijack cellular metabolism is well known, as for CMV, HSV, HIV, vaccinia virus, and many others, as reviewed 39 . This occurs either to facilitate viral replication and virion assembling or to evade local immune responses.…”

Section: Discussionmentioning

confidence: 98%

SARS-CoV-2 Infection Impacts Carbon Metabolism and Depends on Glutamine for Replication in Syrian Hamster Astrocytes

Oliveira

Angelo

Yamamoto

et al. 2021

Preprint

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Coronaviruses belong to a well-known family of enveloped RNA viruses and are the causative agent of the common cold. Although the seasonal coronaviruses do not pose a threat to human life, three members of this family, i.e., SARS-CoV, MERS-CoV and recently, SARS-CoV2, may cause severe acute respiratory syndrome and lead to death. Unfortunately, COVID-19 has already caused more than 4.4 million deaths worldwide. Although much is better understood about the immunopathogenesis of the lung disease, important information about systemic disease is still missing, mainly concerning neurological parameters. In this context, we sought to evaluate immunometabolic changes using in vitro and in vivo models of hamsters infected with SARS-CoV-2. Here we show that, besides infecting hamsters astrocytes, SARS-CoV-2 induces changes in protein expression and metabolic pathways involved in carbon metabolism, glycolysis, mitochondrial respiration, and synaptic transmission. Interestingly, many of the differentially expressed proteins are concurrent with proteins that correlate with neurological diseases, such as Parkinsons's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Metabolic analysis by high resolution real-time respirometry evidenced hyperactivation of glycolysis and mitochondrial respiration. Further metabolomics analysis confirmed the consumption of many metabolites, including glucose, pyruvate, glutamine, and alpha ketoglutarate. Interestingly, we observed that glutamine was significantly reduced in infected cultures, and the blockade of mitochondrial glutaminolysis significantly reduced viral replication and pro-inflammatory response. SARS-CoV-2 was confirmed in vivo as hippocampus, cortex, and olfactory bulb of intranasally infected hamsters were positive for viral genome several days post-infection. Altogether, our data reveals important changes in overall protein expression, mostly of those related to carbon metabolism and energy generation, causing an imbalance in important metabolic molecules and neurotransmitters. This may suggest that some of the neurological features observed during COVID-19, as memory and cognitive impairment, may rely on altered energetic profile of brain cells, as well as an unbalanced glutamine/glutamate levels, whose importance for adequate brain function is unquestionable.

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“…ALPK1 and TIFA are closely downstream of rs112641600 and both have adaptive and innate signal transduction roles and pro-inflammatory functions [ 28 ]. MSR1 , upstream of rs118072448, is a macrophage scavenger receptor and implicated in a broad range of disease types including host viral defence [ 29 ] and PSAT1 is associated with glutamine metabolic reprogramming by SARS-CoV-2 and viral mRNA translation [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a clinical and genetic model for predicting risk of severe COVID-19

2021

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Clinical and genetic risk factors for severe coronavirus disease 2019 (COVID-19) are often considered independently and without knowledge of the magnitudes of their effects on risk. Using severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positive participants from the UK Biobank, we developed and validated a clinical and genetic model to predict risk of severe COVID-19. We used multivariable logistic regression on a 70% training dataset and used the remaining 30% for validation. We also validated a previously published prototype model. In the validation dataset, our new model was associated with severe COVID-19 (odds ratio per quintile of risk = 1.77, 95% confidence interval (CI) 1.64–1.90) and had acceptable discrimination (area under the receiver operating characteristic curve = 0.732, 95% CI 0.708–0.756). We assessed calibration using logistic regression of the log odds of the risk score, and the new model showed no evidence of over- or under-estimation of risk (α = −0.08; 95% CI −0.21−0.05) and no evidence or over-or under-dispersion of risk (β = 0.90, 95% CI 0.80–1.00). Accurate prediction of individual risk is possible and will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.

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SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

Cited by 44 publications

References 135 publications

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

SARS-CoV-2 Infection Impacts Carbon Metabolism and Depends on Glutamine for Replication in Syrian Hamster Astrocytes

Development and validation of a clinical and genetic model for predicting risk of severe COVID-19

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