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    The McMaster Department of Philosophy has now put together the following notice commemorating Barry: Barry Allen: A Philosophical Life Barry…

Is glucose metabolism key to cytokine storms?

Brian Leiter

The headline of this article overstates the findings, but they may well be significant (and would explain why diabetes is a comorobidity for COVID-19 infections):

During an infection, the body’s immune system ramps up the release of molecules called cytokines, which circulate in the blood stream like messengers calling upon immune cells to come and join the fight. In some patients, for largely inexplicable reasons, this battle cry continues even after the invading pathogen begins to retreat….Such a sustained excessive cytokine release, or storm, is the cause of death in a variety of infectious diseases including the flu, COVID-19, Ebola, and sepsis….

The transcription factor interferon regulatory factor 5 (IRF5) is critical for pro-inflammatory cytokine production and, if it is genetically deleted in mice, the animals are protected against influenza-induced cytokine storms. The inflammatory response to influenza infections is also known to drive up glucose metabolism, in part so that immune cells have the necessary energy to mount a strong response, and also because the virus needs the sugar to replicate….

Shi Liu of the State Key Laboratory of Virology at Wuhan University and colleagues now link these threads, identifying a specific glucose metabolism pathway that is required for activating IRF5-induced cytokine production in cells and mice. This so-called hexosamine biosynthesis pathway, a well-known metabolic process, is also required for viral replication, they show.

Hexosamine biosynthesis starts with glucose and results in an end product called uridine diphosphate N-acetylglucosamine (UDP-GlcNAc)—pronounced UDP-GlickNack. This nucleotide sugar is sometimes added to proteins—a process called O-GlcNAcylation—to modify their activity. Liu’s team now shows that O-GlcNAcylation of IRF5 is necessary for the transcription factor’s cytokine-producing activity.

Genetically deleting the enzyme that performs O-GlcNAcylation, called OGT, or IRF5 itself inhibited inflammatory cytokine production as well as viral replication in mice and cells. The knockouts also improved the animals’ survival of infection, suggesting the two factors may be targets for future therapies.

The team also showed that patients infected with influenza have higher blood glucose levels and more O-GlcNacylation of IRF5 than healthy controls. Furthermore, blood glucose levels correlated tightly with levels of inflammatory cytokines.

(Thanks to Dr. David Ozonoff for the pointer.)

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3 responses to “Is glucose metabolism key to cytokine storms?”

  1. Charlie

    This is not my area of expertise and someone can correct me if I'm wrong, I work with prokaryotes which use UDP-GlcNAc for cell walls, but I found the linked article a little confusing because based on the journal article I think the argument is that higher glucose metabolism is associated with cytokine storms.

    Diabetes would mean lower glucose metabolism. The higher blood glucose levels wouldn't be causative, but correlate to increased glucose metabolism; high blood glucose in diabetes is a result of not getting glucose into cells not higher glucose metabolism (glycogen from the liver being turned into glucose and being released into thr blood stream).

    Perhaps a lower glucose metabolism reduces cytokine production (i.e., diabetes) resulting in reduced ability to deal with infection, whereas an overactive glucose metabolism produces cytokine storms (over reactive attempt to deal with an infection). I would think the comorbidity issue with diabetes could easily come from other issues, because a quick literature search suggests diabetes is related to reduce lung function, e.g., doi: 10.1900/RDS.2012.9.23.

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  2. David Ozonoff

    Charlie: You clearly know a lot more about GlcNAc than I do, so I don't really know how to respond to your specific points. On the non-specific level, my general take is that there is evidence that dysregulated networks, that include glucose metabolism, is potentially important in cytokine storm, something I consider plausible, but that's all. As a researcher yourself you know how often things like this seem promising only to see them fade in importance, so we'll have to see how this sorts out. In general, though, runaway behavior like cytokine storm seems to be a signal that a complex system has run off the rails and this suggests that glucose metabolism is involved, very plausible given the sudden increase in energy this requires. Not clear how this does or does not relate to diabetes and its several sources.

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  3. Robert Lee

    It is probably worth pointing out as background that "cytokine storm" and sepsis are just about the same thing and sepsis can crop up from many infections rather than being an infectious disease itself, contrary to the quote.

    A common example of a progression to death for a respiratory infection is pneumonia -> sepsis -> septic shock -> organ failure -> heart failure.

    The question is if COVID-19 has a specific link to sepsis/cytokine storms beyond it becoming a severe respiratory infection which can result in sepsis. To paraphrase David Ozonoff above, tracking causality through a complex system is tricky.

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