Host metabolic reprogramming in response to SARS-Cov-2 infection

Moolamalla, S.T.R.; Chauhan, Ruchi; Vinod, P. K.

doi:10.1101/2020.08.02.232645

Cited by 12 publications

(11 citation statements)

References 78 publications

(68 reference statements)

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“…This lymphopenia may be connected to dysfunctional cell metabolism of different immune effector cells. Recent gene expression studies have also shown evidence for metabolic changes in COVID-19 patients (Gardinassi et al 2020;Moolamalla et al 2020). However, few studies have investigated how metabolic processes might be correlated to the host immune response to SARS-CoV-2 infection.…”

Section: Resultsmentioning

confidence: 99%

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism

Policard

Jain

Rego

et al. 2021

Preprint

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The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F7 and RB1, suggesting a mechanism by which cancer may arise in patients infected with SARS-CoV2. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.

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Section: Resultsmentioning

confidence: 99%

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism

Policard

Jain

Rego

et al. 2021

Preprint

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“…For example, the Warburg effect has been identified as having a key role in SARS-CoV-2 replication and associated inflammatory response [46]. Others have demonstrated the downregulation of the pentose phosphate pathway [47]. While others have reported the role of nicotinate metabolism linked to inflammatory signals [33].…”

Section: Specificity Of Sars-cov-2 Virus Isolatesmentioning

confidence: 99%

Metabolic Profiling from an Asymptomatic Ferret Model of SARS-CoV-2 Infection

et al. 2021

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Coronavirus disease (COVID-19) is a contagious respiratory disease that is causing significant global morbidity and mortality. Understanding the impact of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection on the host metabolism is still in its infancy but of great importance. Herein, we investigated the metabolic response during viral shedding and post-shedding in an asymptomatic SARS-CoV-2 ferret model (n = 6) challenged with two SARS-CoV-2 isolates. Virological and metabolic analyses were performed on (minimally invasive) collected oral swabs, rectal swabs, and nasal washes. Fragments of SARS-CoV-2 RNA were only found in the nasal wash samples in four of the six ferrets, and in the samples collected 3 to 9 days post-infection (referred to as viral shedding). Central carbon metabolism metabolites were analyzed during viral shedding and post-shedding periods using a dynamic Multiple Reaction Monitoring (dMRM) database and method. Subsequent untargeted metabolomics and lipidomics of the same samples were performed using a Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-QToF-MS) methodology, building upon the identified differentiated central carbon metabolism metabolites. Multivariate analysis of the acquired data identified 29 significant metabolites and three lipids that were subjected to pathway enrichment and impact analysis. The presence of viral shedding coincided with the challenge dose administered and significant changes in the citric acid cycle, purine metabolism, and pentose phosphate pathways, amongst others, in the host nasal wash samples. An elevated immune response in the host was also observed between the two isolates studied. These results support other metabolomic-based findings in clinical observational studies and indicate the utility of metabolomics applied to ferrets for further COVID-19 research that advances early diagnosis of asymptomatic and mild clinical COVID-19 infections, in addition to assessing the effectiveness of new or repurposed drug therapies.

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“…Our data are in agreement with previous results showing virus-induced metabolic reprogramming in the host. The increased abundance of metabolites and their pathways, such as free fatty acids and amino acids, was correlated to the increase in viral proliferation, since these biomolecules can act as building blocks and fuel for this process [141][142][143] .…”

Section: Additional Informationmentioning

confidence: 99%

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

Pérez

Pimentel

Fuzo

et al. 2021

Preprint

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Cytokine storms and hyperinflammation, potentially controlled by glucocorticoids, occur in COVID-19; the roles of lipid mediators and acetylcholine (ACh) and how glucocorticoid therapy affects their release in Covid-19 remain unclear. Blood and bronchoalveolar lavage (BAL) samples from SARS-CoV-2- and non-SARS-CoV-2-infected subjects were collected for metabolomic/lipidomic, cytokines, soluble CD14 (sCD14), and ACh, and CD14 and CD36-expressing monocyte/macrophage subpopulation analyses. Transcriptome reanalysis of pulmonary biopsies was performed by assessing coexpression, differential expression, and biological networks. Correlations of lipid mediators, sCD14, and ACh with glucocorticoid treatment were evaluated. This study enrolled 190 participants with Covid-19 at different disease stages, 13 hospitalized non-Covid-19 patients, and 39 healthy-participants. SARS-CoV-2 infection increased blood levels of arachidonic acid (AA), 5-HETE, 11-HETE, sCD14, and ACh but decreased monocyte CD14 and CD36 expression. 5-HETE, 11-HETE, cytokines, ACh, and neutrophils were higher in BAL than in circulation (fold-change for 5-HETE 389.0; 11-HETE 13.6; ACh 18.7, neutrophil 177.5, respectively). Only AA was higher in circulation than in BAL samples (fold-change 7.7). Results were considered significant at P<0.05, 95%CI. Transcriptome data revealed a unique gene expression profile associated with AA, 5-HETE, 11-HETE, ACh, and their receptors in Covid-19. Glucocorticoid treatment in severe/critical cases lowered ACh without impacting disease outcome. We first report that pulmonary inflammation and the worst outcomes in Covid-19 are associated with high levels of ACh and lipid mediators. Glucocorticoid therapy only reduced ACh, and we suggest that treatment may be started early, in combination with AA metabolism inhibitors, to better benefit severe/critical patients.

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Host metabolic reprogramming in response to SARS-Cov-2 infection

Cited by 12 publications

References 78 publications

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism

Metabolic Profiling from an Asymptomatic Ferret Model of SARS-CoV-2 Infection

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

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