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            -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

Wang, Qiming; Fang, Peining; He, Rui; Li, Mengqi; Yu, Haisheng; Zhou, Li; Yu, Yongsheng; Wang, Xinghuan; Yuan, Rong; Zhang, Yi; Chen, Aidong; Peng, Nanfang; Lin, Yong; Lu, Mengji; Zhu, Ying; Peng, Guoping; Rao, Liqun; Shi, Lei

doi:10.1126/sciadv.aaz7086

Cited by 102 publications

(104 citation statements)

References 40 publications

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“…43,44 Both preclinical models and clinical data from the H1N1 pandemic also suggest that diabetes, particularly when associated with hyperglycemia and glycemic variability, is associated with worse outcomes after infection with influenza. 45,46 Glycemic variability has similarly been found to be associated with outcomes in type 2 diabetics with COVID-19. 47 This suggests that regardless of the virus type, taking steps to improve population metabolic and immune health will play a crucial role in reducing the impact of future pandemics.…”

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confidence: 98%

Metabolic health and lifestyle medicine should be a cornerstone of future pandemic preparedness

Wood

Johannsson

2020

Lifestyle Medicine

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Metabolic health and lifestyle medicine should be a cornerstone of future pandemic preparedness The recent impact of SARS-CoV-2 and coronavirus disease 2019 (COVID-19) has shown major differences in infrastructure and approach across healthcare systems worldwide. One thing we can already be certain of is that governments and policy makers worldwide will place a greater focus on pandemic preparedness in the future. However, as well as ensuring that robust pipelines for rapid test, highly effective treatment or vaccine, and personal protective equipment (PPE) production are in place, we must address underlying resilience and susceptibility of our populations to infectious disease. Although the true spread and case fatality rate of SARS-CoV-2 may not be known for several months or even years, what is becoming increasingly clear is the significant degree to which underlying conditions associated with suboptimal metabolic health appear to be associated with poor outcomes in those with COVID-19. 1-4 Considering the nature of these underlying conditions such as obesity and hypertension, lifestylebased approaches are likely to be one of our best tools in order to address ongoing and future disease burden during pandemics. Based on the largest available studies at time of writing, the comorbidities particularly associated with hospitalization and poor outcome in patients with COVID-19 are age, obesity, hypertension, and diabetes. For instance, one study in New York City found that, of 5700 patients hospitalized with COVID-19, 57%, 42%, and 34% had hypertension, obesity, and diabetes, respectively. 1 Of 72 314 cases from the Chinese Center for Disease Control and Prevention, reported case fatality rate was elevated in those with comorbid conditions: at least 10% for cardiovascular diseases, 7% for diabetes, and 6% for hypertension. 2 Importantly, however, the diabetes diagnoses associated with increased risk have not routinely been separated by type (1 or 2) or duration, and this is a key area of future research. As outlined below, with metabolic derangement (eg, systemic insulin resistance) and hyperglycemia potentially underlying changes in the immune system seen in the comorbid conditions associated with worse COVID-19 outcome, it is possible that the well-controlled type 1 diabetic is not at increased risk. In studies of COVID-19 patients requiring invasive mechanical ventilation in Italy and New York City, the latter as a preprint at time of writing, both age and obesity were significant contributors to risk, with the mechanical disadvantage of ventilation in obese patients a potential contributor. 3,4 In the United Kingdom, the This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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mentioning

confidence: 98%

Metabolic health and lifestyle medicine should be a cornerstone of future pandemic preparedness

Wood

Johannsson

2020

Lifestyle Medicine

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“…Due to the resource restriction, our study validated the effects of supplemented metabolites or pharmacological inhibitors in regulating the CRS induced by SARS-CoV-2 infection using the ex-vivo model of PBMCs isolated from the infected rhesus macaques. Although the isolated PBMCs ex vivo models has been extensively used for the evaluation of cytokine release 44,45 , it would have been ideal to perform such analyses in rhesus macaque in vivo models. We tested the impacts of metabolism intervening on the immunological responses in the heterogenous PBMCs.…”

Section: Discussionmentioning

confidence: 99%

Host metabolite-cytokine correlation landscape in SARS-CoV-2 infection

Xiao

Nie

Pang

et al. 2020

Preprint

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The systemic cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. It has been well-known that metabolism plays a role in modulating the immune responses in infectious diseases. Yet, how the host metabolism correlates with CRS in COVID-19 patients and how the perturbed metabolites affect the cytokine release remains unclear. Here, we performed both metabolomics and cytokine/chemokine profiling on serum samples from the same cohort of healthy controls, mild and severe COVID-19 patients and delineated the global metabolic and immune response landscape along disease progression. Intriguingly, the correlation analysis revealed the tight link between metabolites and proinflammatory cytokines and chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, implying the potential regulatory role of arginine metabolism, tryptophan metabolism, and purine metabolism in hyperinflammation. Importantly, we demonstrated that targeting metabolism markedly modulated the proinflammatory cytokines release by PBMCs isolated from SARS-CoV-2-infected rhesus macaques ex vivo. Beyond providing a comprehensive resource of metabolism and immunology data of SARS-CoV-2 infection, our study showed that metabolic alterations can be potentially exploited to develop novel strategy for the treatment of fatal CRS in COVID-19.

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“…Reactome pathway enrichment also uniquely reveals several roles for OGT TPR interactors in viral infection, nuclear import, and processing. OGT has been demonstrated to play a role in a limited number of specific viral infections 38,51 but these enriched pathways point to a potentially broader role for OGT and its interactors more generally in viral infection. Interactors are also enriched in the reactome pathway "regulation of glucokinase by glucokinase regulatory protein".…”

Section: Ontology Analyses Of the Ogt Tpr-interactomementioning

confidence: 99%

Generation of an Unbiased Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

Stephen

Praissman

Wells

2020

Preprint

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The O-GlcNActransferase (OGT) is localized to the nucleus and cytoplasm where it regulates nucleocytoplasmic proteins by modifying serine and threonine residues with a non-extended monosaccharide, b-N-Acetyl-Glucosamine (O-GlcNAc). With thousands ofknown O-GlcNAcmodifiedproteinsbut only oneOGTencoded in the mammalian genome, a prevailing question is howOGTselects its substrates. Prior work has indicated that theN-terminaltetratricopeptide repeat (TPR) domain of OGT, rather than itsC-terminalcatalytic domain, is responsible forsubcellular targeting andsubstrate selection.An additional impetus for exploring the OGT TPR domain interactome is the fact that missense mutations inOGTassociated with X-linked intellectual disability (XLID) are primarily localized to the TPR domain without substantial impact on activity or stability of the enzyme.Therefore, we adapted theBioIDlabeling method to identify interactors of a TPR-BirA* fusion protein in HeLa cells. We identified 115high confidenceinteractors representing both known and novel O-GlcNAcmodified proteins and OGT interactors. The TPR interactors are highly enriched in processes in which OGT has a known role (e.g. chromatin remodeling, cellular survival of heat stress, circadian rhythm), as well as processesin which OGT has yet to be implicated (e.g. pre-mRNA processing). Importantly,the identified TPR interactors are involved in several disease states but most notably are highly enriched in pathologies featuring intellectual disability.Theseproteinsrepresent candidateinteractors that may underlie the mechanismby which mutations in OGT lead to XLID. Furthermore, the identified interactors provide additional evidence of the importance of the TPR domain for OGT targeting and/or substrate selection.Thus, this defined interactome for the TPR domain of OGT serves as ajumping off point for future researchexploringthe role of OGT, the TPR domain, and its protein interactorsin multiple cellular processes and disease mechanisms, including intellectual disability.

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O -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

Cited by 102 publications

References 40 publications

Metabolic health and lifestyle medicine should be a cornerstone of future pandemic preparedness

Metabolic health and lifestyle medicine should be a cornerstone of future pandemic preparedness

Host metabolite-cytokine correlation landscape in SARS-CoV-2 infection

Generation of an Unbiased Interactome for the Tetratricopeptide Repeat Domain of O-GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

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