Reprogramming of glucose metabolism in virus infected cells

Goyal, Priya; Rajala, Maitreyi S.

doi:10.1007/s11010-023-04669-4

Cited by 14 publications

(5 citation statements)

References 79 publications

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“…As a consequence, virus replication could also be impeded compared to cells infected at a late exponential growth phase with a surplus of substrate supply. Furthermore, OVs in particular, are dependent on the host cell glycolysis, and delayed reactivation of host cell glycolysis modulated by rVSV‐NDV after infection could further negatively impact virus replication (Goyal & Rajala, 2023). For production at 130 rpm, glucose limitation and the high lactate concentration at 48 hpi, before maximum titers were reached, most likely had a negative impact on virus replication.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a quail suspension cell line for production of a fusogenic oncolytic virus

Göbel

Jaén

Fernandes

et al. 2023

Biotech & Bioengineering

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The development of efficient processes for the production of oncolytic viruses (OV) plays a crucial role regarding the clinical success of virotherapy. Although many different OV platforms are currently under investigation, manufacturing of such viruses still mainly relies on static adherent cell cultures, which bear many challenges, particularly for fusogenic OVs. Availability of GMP‐compliant continuous cell lines is limited, further complicating the development of commercially viable products. BHK21, AGE1. CR and HEK293 cells were previously identified as possible cell substrates for the recombinant vesicular stomatitis virus (rVSV)‐based fusogenic OV, rVSV‐NDV. Now, another promising cell substrate was identified, the CCX.E10 cell line, developed by Nuvonis Technologies. This suspension cell line is considered non‐GMO as no foreign genes or viral sequences were used for its development. The CCX.E10 cells were thus thoroughly investigated as a potential candidate for OV production. Cell growth in the chemically defined medium in suspension resulted in concentrations up to 8.9 × 106 cells/mL with a doubling time of 26.6 h in batch mode. Cultivation and production of rVSV‐NDV, was demonstrated successfully for various cultivation systems (ambr15, shake flask, stirred tank reactor, and orbitally shaken bioreactor) at vessel scales ranging from 15 mL to 10 L. High infectious virus titers of up to 4.2 × 108 TCID50/mL were reached in orbitally shaken bioreactors and stirred tank reactors in batch mode, respectively. Our results suggest that CCX.E10 cells are a very promising option for industrial production of OVs, particularly for fusogenic VSV‐based constructs.

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Section: Resultsmentioning

confidence: 99%

Characterization of a quail suspension cell line for production of a fusogenic oncolytic virus

Göbel

Jaén

Fernandes

et al. 2023

Biotech & Bioengineering

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“…Production of viral particles is a highly energy-intense process and infection has been shown to increase glucose-dependence of cells 19 . We therefore considered that glucose restriction hampers viral replication by preventing the cell from meeting its metabolic requirements.…”

Section: Glucose Restriction Impairs Viral Replication In Vitro By Re...mentioning

confidence: 99%

An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response

Šestan,

Mikašinović,

Benić

et al. 2024

Nat Immunol

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Viral infection makes us feel sick. The extent of these changes to our metabolism are relative to the severity of disease. Whether blood glucose levels are subject to infection-induced modulation is largely unknown. Here we show that strong, non-lethal infection restricts systemic glucose availability which promotes the antiviral IFN-I response. Following systemic viral infection of mice, we find that IFNγ produced by γδ T cells directly stimulates pancreatic β-cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens endogenous glucose output by the liver. Glucose restriction enhances type-I interferon production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, which explains why people with metabolic disease are more susceptible to viral infection. MAINA reduced sense of wellbeing, commonly referred to as 'feeling sick', is one of the best known yet most poorly understood symptoms of viral infection. Whereas it is perceived as pathological, 'feeling sick' is the result of a carefully regulated set of metabolic adaptations mediated by the immune system. Its proposed purpose is to optimize nutrient availability to the immune system 1, 2, 3 , whilst impairing viral replication 4, 5 . Adjusting systemic metabolism is not without risk as it impacts vital functions of the body.The level of modulation is therefore proportional to the severity of infection and thus the risk that is acceptable to counter a pathogenic threat 3 . A key parameter of which differential regulation depends on the intensity of infection is blood glucose. Blood glucose concentrations must be retained between defined threshold values to prevent hypoglycemic coma and hyperglycemia-induced tissue damage 6 .Multiple regulatory mechanisms exist, but the hormone insulin plays a central role in glycemic control. If glucose levels rise, insulin is produced by pancreatic β-cells which stimulates glucose uptake and storage in organs such as adipose tissue and skeletal muscle and impairs glucose release by the liver 7 . Previously, we showed that following mild infection the immune system reduces insulin sensitivity of skeletal muscle cells. As a result, the pancreas compensated through increased insulin production which retained blood glucose levels within threshold values but also directly boosted the CD8 + T cell response 8, 9 . Following Control 2x10 7 IFU LCMV FPG 3 days p. i.

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“…We observed a significant increase in glucose uptake and lactate secretion for all tested cell lines (Figure 1B), indicating increased glycolytic activity. This phenomenon is known for various bacterial and viral infections, especially in immune cells, presumably to provide biosynthetic intermediates for the synthesis of nucleotides, amino acids and lipids to support host cell proliferation [29][30][31].…”

Section: P Aeruginosa Bmvs Induce Rapid Metabolic Reprogramming By Mo...mentioning

confidence: 99%

Bacterial membrane vesicles ofPseudomonas aeruginosaactivate AMPK signaling through inhibition of mitochondrial complex III

Müller,

Kretschmer,

Opitsch

et al. 2024

Preprint

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Bacterial membrane vesicles (BMVs) are secreted by many pathogenic bacteria and known to stimulate various host responses upon infection, thereby contributing to the pathogenicity of bacterial pathogens likePseudomonas aeruginosa. While the effects of BMVs on host immune responses are well studied, little is known about their impact on cell metabolism and mitochondrial respiration. Here, we show thatP. aeruginosaBMVs (1) reprogram cell metabolism of human lung cells, (2) negatively affect mitochondrial respiration by (3) specifically inhibiting complex III of the electron transport chain leading to (4) the activation of AMP-activated protein kinase (AMPK) signaling which in turn results in (5) AMPK-dependent inhibition of global protein synthesis.

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Reprogramming of glucose metabolism in virus infected cells

Cited by 14 publications

References 79 publications

Characterization of a quail suspension cell line for production of a fusogenic oncolytic virus

Characterization of a quail suspension cell line for production of a fusogenic oncolytic virus

An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response

Bacterial membrane vesicles ofPseudomonas aeruginosaactivate AMPK signaling through inhibition of mitochondrial complex III

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