In a new study, researchers from Wuhan University, Hunan Agricultural University, Zhejiang University, Hubei University of technology, Nanjing Medical University, Chongqing Medical University and Duisburg Essen University in Germany have shown that glucose metabolism is responsible for the often fatal inflammatory response known as cytokine storm Storm) - the driving force generated. The results identify potential drug targets for future treatment and may partly explain the increased risk of serious complications and death in patients with diabetes due to influenza and other infections. Preliminary data show that the same is true for covid-19. The relevant research results were published in the April 15, 2020 Journal of science advances, and the title of the paper is "O-GlcNAc transfer promotion influenza A virus – induced cytokine store by targeting interaction regulatory factor – 5".
The picture is from science advanced, 15 APR 2020, DOI: 10.1126/sciadv.aaz7086.
"This is a good study based on previous findings from influenza and other viral systems," said Paul Thomas, an immunologist at St Jude's children's research hospital in the United States, who was not involved in the new study. It does go deep into the molecular mechanism of metabolic regulation of inflammation and viral replication. "
In the process of infection, the immune system in the body will increase the release of cytokines, which circulate in the blood stream like a messenger molecule calling immune cells to fight. In some patients, for largely unexplained reasons, the battle continues even as the invading pathogen begins to retreat.
Haitao Wen, an infection and Immunology researcher at Ohio State University School of medicine, said: "the starting point of this inflammatory response is to resist infection, but if it is not well controlled, it will cause collateral damage to tissues (especially lung tissues) at a later stage." This persistent excess cytokine release, or storm, is responsible for deaths from a variety of infectious diseases, including influenza, covid-19, Ebola infection, and sepsis.
Little is known about what causes uncontrolled proliferation of cytokine production, but there are some clues. A transcription factor called interferon regulatory factor 5 (IRF5) is essential for pro-inflammatory cytokine production. If this gene is removed from mice, these mice can be protected from cytokine storms caused by influenza virus infection. Thomas explained that the inflammatory response to influenza virus infection can also promote glucose metabolism, in part because immune cells have the necessary energy to produce a strong response, which is also because glucose is needed for virus replication.
In the new study, Dr. Shi Liu and colleagues from the State Key Laboratory of Virology, Wuhan University, who are co authors of the paper, now link these clues and identify a specific glucose metabolism pathway necessary to activate IRF5 induced cytokine production in cells and mice. As a well-known metabolic process, this so-called hexosamine biosynthesis pathway is also necessary for viral replication.
The biosynthesis of hexosamine begins with glucose and the final product is UDP GlcNAc. This nucleotide sugar is sometimes added to proteins - a process called o-glcnacylation glycosylation - to modify the activity of these proteins. Dr. Liu and his team now find that o-glcnacylation glycosylation of IRF5 is necessary for the production of cytokines of this transcription factor.
The elimination of O-GlcNAc glycosyltransferase (OGT), which performs o-glcnacylation glycosylation, or the elimination of IRF5 itself can inhibit the production of inflammatory cytokines and virus replication in mice and cells. These knockouts also improved infection survival in these mice, suggesting that these two factors may be targets for future treatment.
The researchers also found that patients with influenza virus had higher blood sugar levels and more IRF5 o-glcn acylation than healthy controls. In addition, the level of blood glucose is closely related to the level of inflammatory cytokines.
These results indicate that "influenza virus infection, increased glucose metabolism and cytokine storm are all linked by o-glcnacylation glycosylation of ifr-5."
Although the study focused on influenza, cytokine storms are also a common cause of death for covid-19, and patients with metabolic disorders, including diabetes, appear to be more prone to such serious complications. "We believe that glucose metabolism can lead to various outcomes of covid-19, because influenza and covid-19 can cause cytokine storms, and patients with diabetes have higher mortality," Liu said in a press release
For flu and covid-19, "the mortality rate for diabetics is definitely higher," Wen said. But, he added, the explanation for this may be more complicated than the idea that the presence of large amounts of glucose fuels this inflammatory response. He said it is likely to be related to glucose metabolism disorders in such people.
Even if there is no diabetes or other obvious underlying diseases, patients may experience cytokine storms. As a result, John teijaro, an immunologist and microbiologist at the Scripps Institute in the US, who was not involved in the new study, said the study "has broad implications.". It also "provides several different potential drug targets for interfering with cytokine storms, such as OGT and IRF5," he said Because inhibiting these potential targets can prevent both cytokine production and virus replication, drugs targeting them may inhibit inflammation, "without damaging host immunity and virus control, which is the highest goal in this field," teijaro said.
reference material:
1.Qiming Wang et al. O-GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5. Science Advances, 15 Apr 2020, doi:10.1126/sciadv.aaz7086.
2.Discovered: Metabolic Mechanism of Cytokine Storms
Https://www.the-scientist.com/news-opinion/discovered-metallic-mechanism-of-cytokine-stores -- 67424cell: cell therapy field observers long press identification QR code, easy attention