*For medical professionals only
Even with the successful delivery of the new coronavirus, our respiratory tract has not had a few good days after the weather turned cold this year. Influenza A viruses and Mycoplasma pneumoniae bombarded in turn, triggering a pandemic of influenza and mycoplasma pneumonia in the autumn and winter. (Don't be confused, mycoplasma is a pathogenic microorganism between bacteria and viruses, not a "new variant of the new coronavirus")
Studies have shown that viral respiratory infections, whether it is the flu or the new coronavirus, have a strong preference for "sugar". Of course, sugar here refers to high blood sugar, and a very significant and still unexplained mysterious phenomenon of type 1 and type 2 diabetes is the increased susceptibility to respiratory infections and even fatal lung infections.
Recently, a paper published in the top journal Nature revealed for the first time the mechanism of susceptibility of diabetic patients to viral respiratory infections, and it turns out that high blood sugar can suppress the combat effectiveness of our lung immune sentinels [1].
Dendritic cells, the immune sentinels of the lungs, have the ability to capture, process, and present pathogen antigens, which can be carried to the lungs to drain lymph nodes (dLNs) to awaken T cells and help us fight off the flu. The team of Eran Elinav of the Weizmann Institute of Science in Israel found that blood glucose has a key regulatory effect on lung dendritic cells, and hyperglycemia can lead to changes in the epigenetics of dendritic cells, thereby causing immune dysfunction and weakening the immune resistance of hyperglycemic mice to viral respiratory infections.
Screenshot of the first page of the paper
According to statistics, the number of people with diabetes worldwide has gradually increased from 108 million in 1980 to more than 500 million today, and is expected to increase to 785 million in 2045 [2]. The increasing burden of disease caused by diabetes, and the emergence of viral respiratory infections are endless, and it is necessary to explore the mystery between them.
Eran Elinav's team first found in mouse experiments that compared with non-diabetic mice, type 1 or type 2 diabetic mice could not be eliminated in time after being infected with pulmonary pathogens such as influenza viruses, and the mortality rate was higher, the lung viral load was higher, the infiltration of lung immune cells was reduced, and the adaptive immune response mediated by T cells and B cells was severely deficient.
The use of insulin supplementation therapy to lower blood sugar can be reversed, helping to improve viral clearance and survival, improve immune response, and control lung damage in influenza-infected diabetic mice.
Lung Infections Exacerbated by Diabetes in Mice (Ins: Insulin Therapy)
What's the problem?
Subsequently, Eran Elinav's team used single-cell RNA sequencing and other technologies to analyze more than 150,000 mouse lung cells to compare the differentially expressed genes between diabetic and non-diabetic mice.
The results showed that after infection with influenza virus, multiple lung dendritic cell subsets of diabetic mice had abnormal gene expression, especially cDC1 subset, which was the most severely damaged immune cell in the lungs of diabetic mice.
Combined with in vitro culture experiments, the researchers found that the cell activity of these lung dendritic cells did not change in vivo or high glucose culture environment (50 mM) in diabetic mice, but the gene expression associated with antigen presentation was down-regulated, the antigen presentation ability was reduced, and the ability to induce T cell immune activation was directly inhibited by high glucose conditions.
Expression of genes associated with immune activation in dendritic cells is inhibited by hyperglycemia
When the injected drug specifically depletes the dendritic cells in their bodies, the antiviral immunity of diabetic mice is not further impaired. On the other hand, if wild-type mice receive dendritic cells from the lungs of influenza-infected diabetic mice, it can be detected that their lungs have a weakened adaptive immune response in the absence of infection, and the ability to clear the virus when infected with influenza is reduced.
These results suggest that dendritic cells in the lungs are a key link between hyperglycemia and influenza susceptibility.
Blood sugar and metabolism can always be linked.
Indeed it is. Further studies have shown that hyperglycemia can regulate the function of dendritic cells in the lungs by altering metabolic processes.
Specifically, under the condition of hyperglycemia, the metabolic pathway of glucose decomposition to acetyl-CoA in lung dendritic cells is enhanced, resulting in excessive histone acetylation and changes in cell chromatin after epigenetic modification, resulting in impaired expression of genes related to immune function in dendritic cells.
Histone acetyltransferase inhibitors (hydrogenated leukolicic acid, ANA) can partially rescue the hyperacetylation of dendritic cells and its effects on T cell immunity, and diabetic mice treated with histone acetyltransferase inhibitors have improved virus clearance after infection with influenza virus.
Histone acetyltransferase inhibitors can partially rescue antiviral immunodeficiency caused by hyperglycemia
In conclusion, this study explains for the first time that diabetic patients are more susceptible to respiratory infections, associated with hyperglycemia disrupting the function of dendritic cells in the lungs.
According to Eran Elinav [2], the results of this study highlight the importance of tight blood glucose control for diabetic patients, especially during viral lung infections, and that reducing hyperglycemia through insulin may improve antiviral immunity.
For patients with diabetes whose blood glucose levels cannot be effectively controlled, the use of drugs to intervene against excessive acetylation of dendritic cells may help to improve the immune dysfunction caused by hyperglycemia and reduce or even prevent serious lung infections, and can also be administered locally by inhalation to minimize side effects and improve effectiveness, which warrants further clinical trials [2].
Bibliography:
[1] Nobs, S.P., Kolodziejczyk, A.A., Adler, L. et al. Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes. Nature (2023). https://doi.org/10.1038/s41586-023-06803-0
[2]https://wis-wander.weizmann.ac.il/life-sciences/why-people-diabetes-are-more-prone-respiratory-risk
The author of this article丨Zhang Aidi