Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?

Laviada-Molina, Hugo; Leal-Berumen, Irene; Rodríguez-Ayala, Ernesto; Bastarrachea, Raúl A.

doi:10.3389/fendo.2020.00514

Cited by 18 publications

(17 citation statements)

References 53 publications

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“…Like cancer cells, the metabolic milieu was rearranged in virus-infected cells to facilitate virus production and replication [ 65 ]. In general, viral infection in mammalian cells shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP production [ 66 ].…”

Section: Introductionmentioning

confidence: 99%

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

et al. 2021

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Purpose Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues. So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-existing diabetes’s pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology. Results SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand the long-term consequences that will affect patients with diabetes who survived COVID-19. Conclusions Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus’s detrimental effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features, supporting a potential role of COVID-19 in the development of diabetes.

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Section: Introductionmentioning

confidence: 99%

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

et al. 2021

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“…Viral infections increase glucose metabolism in macrophages, involving activation of the hexosamine biosynthesis pathway and associated enzyme O-GlcNAc transferase, as already proposed for SARS-CoV-2 (105). Thus, increased activation of IRF5 by K63polyubiquitination may turn out to provide an important link between so-called "metabolic inflammation" and increased severity of the cytokine response in COVID-19 (105,106). Infection with influenza virus markedly increases GlcNAcylation of IRF5 at serine 430 in human macrophages, which is essential for K63polyubiquitination of the same residue that activates IRF5, thus promoting proinflammatory cytokine expression and possibly increased viral replication (26).…”

Section: The Metabolic Dimension and Covid-19 Comorbiditiesmentioning

confidence: 71%

“…The well-established paradigm that innate immunity programs adaptive immunity applies not only in microbial infection (117) but also autoimmunity (118,119) and cancer, being generally tolerogenic in the latter. "Cytokine storm" of COVID-19 illustrates the dangers of a fundamental mismatch between increased proinflammatory innate signaling and a defective adaptive response, insufficient to kill the virus or prevent spread (105), thus failing to abort innate immune activation. This review has presented evidence that IRF5 is a key "hub" molecule determining the normal balance between innate and adaptive immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Maintaining the M1 phenotype is energy-consuming and achieved by a "metabolic switch" from oxidative to glycolytic metabolism during M2-to-M1 polarization (41). Viral infections increase glucose metabolism in macrophages, involving activation of the hexosamine biosynthesis pathway and associated enzyme O-GlcNAc transferase, as already proposed for SARS-CoV-2 (105). Thus, increased activation of IRF5 by K63polyubiquitination may turn out to provide an important link between so-called "metabolic inflammation" and increased severity of the cytokine response in COVID-19 (105,106).…”

Section: The Metabolic Dimension and Covid-19 Comorbiditiesmentioning

confidence: 93%

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Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

Stoy

2021

Front. Immunol.

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Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19.

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“…Likewise, Krausgruber et al also showed that IRF5 was involved in TNF-α secretion by human dendritic cells [ 56 ]. Interestingly, in a recently published review, Laviada-Molina et al argued that overproduction of deleterious cytokines called “cytokine storm” following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was related to the increased glucose metabolism and IRF5 triggering, leading to hyperinflammation due to a massive inflammatory gene overexpression, induction of the ER stress, and a dysregulated cytokine profile, with increased risks of vascular hyperpermeability and multiorgan failure [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway

Al-Rashed

Sindhu

Arefanian

et al. 2020

Cells

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Repetitive intermittent hyperglycemia (RIH) is an independent risk factor for complications associated with type-2 diabetes (T2D). Glucose fluctuations commonly occur in T2D patients with poor glycemic control or following intensive therapy. Reducing blood glucose as well as glucose fluctuations is critical to the control of T2D and its macro-/microvascular complications. The interferon regulatory factor (IRF)-5 located downstream of the nutrient sensor toll-like receptor (TLR)-4, is emerging as a key metabolic regulator. It remains unclear how glucose fluctuations may alter the IRF5/TLR4 expression and inflammatory responses in monocytes/macrophages. To investigate this, first, we determined IRF5 gene expression by real-time qRT-PCR in the white adipose tissue samples from 39 T2D and 48 nondiabetic individuals. Next, we cultured THP-1 macrophages in hypo- and hyperglycemic conditions and compared, at the protein and transcription levels, the expressions of IRF5, TLR4, and M1/M2 polarization profile and inflammatory markers against control (normoglycemia). Protein expression was assessed using flow cytometry, ELISA, Western blotting, and/or confocal microscopy. IRF5 silencing was achieved by small interfering RNA (siRNA) transfection. The data show that adipose IRF5 gene expression was higher in T2D than nondiabetic counterparts (p = 0.006), which correlated with glycated hemoglobin (HbA1c) (r = 0.47/p < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (r = 0.23/p = 0.03), tumor necrosis factor (TNF)-α (r = 0.56/p < 0.0001), interleukin (IL)-1β (r = 0.40/p = 0.0009), and C-C motif chemokine receptor (CCR)-2 (r = 0.49/p < 0.001) expression. IRF5 expression in macrophages was induced/upregulated (p < 0.05) by hypoglycemia (3 mM/L), persistent hyperglycemia (15 mM/L–25 mM/L), and RIH/glucose fluctuations (3–15 mM/L) as compared to normoglycemia (5 mM/L). RIH/glucose fluctuations also induced M1 polarization and an inflammatory profile (CD11c, IL-1β, TNF-α, IL-6, and monocyte chemoattractant protein (MCP)-1) in macrophages. RIH/glucose fluctuations also drove the expression of matrix metalloproteinase (MMP)-9 (p < 0.001), which is a known marker for cardiovascular complication in T2D patients. Notably, all these changes were counteracted by IRF5 silencing in macrophages. In conclusion, RIH/glucose fluctuations promote the M1 polarization and inflammatory responses in macrophages via the mechanism involving TLR4-IRF5 pathway, which may have significance for metabolic inflammation.

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Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?

Cited by 18 publications

References 53 publications

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway

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