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.)
