Discovered: Metabolic Mechanism of Cytokine Storms

[Gert van der Hoek]

By studying influenza in mice and cells, researchers identify a glucose metabolism pathway critical to the dysregulated immune response that kills many infectious disease patients, including those with COVID-19.

Astudy of influenza infection shows that glucose metabolism is a driving force underlying the development of the often deadly inflammatory response known as a cytokine storm, according to a report in Science Advances today (April 15). The results, which identify potential drug targets for future treatments, may partly explain why patients with diabetes are at an increased risk of serious complications and death from influenza and other infections. Preliminary data indicate this appears to be the case for COVID-19 as well.

“The initial point of this inflammatory response is to counteract infection,” says Haitao Wen, who is an infection and immunity researcher at the Ohio State University College of Medicine and was not involved in the study, “but if it is not well controlled, then at the later stage it will cause collateral damage to tissues, especially lung tissue.” 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 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.

 

[Gert van der Hoek]

RESEARCH ARTICLEVIROLOGY

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

Abstract


In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)–associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)–induced cytokine storm.

O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor–5 (IRF5), leading to O-GlcNAcylation of IRF5 on serine-430. O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production.

Analysis of clinical samples revealed that IRF5 is O-GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients.

We identified a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.


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