Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes

Nobs, Samuel Philip and Kolodziejczyk, Aleksandra A. and Adler, Lital and Horesh, Nir and Botscharnikow, Christine and Herzog, Ella and Mohapatra, Gayatree and Hejndorf, Sophia and Hodgetts, Ryan-James and Spivak, Igor and Schorr, Lena and Fluhr, Leviel and Kviatcovsky, Denise and Zacharia, Anish and Njuki, Suzanne and Barasch, Dinorah and Stettner, Noa and Dori-Bachash, Mally and Harmelin, Alon and Brandis, Alexander and Mehlman, Tevie and Erez, Ayelet and He, Yiming and Ferrini, Sara and Puschhof, Jens and Shapiro, Hagit and Kopf, Manfred and Moussaieff, Arieh and Abdeen, Suhaib K. and Elinav, Eran (2023) Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes. Nature. ISSN 0028-0836

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Abstract

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.

Item Type: Article
Subjects: Science Global Plos > Geological Science
Depositing User: Unnamed user with email support@science.globalplos.com
Date Deposited: 14 Dec 2023 10:52
Last Modified: 14 Dec 2023 10:52
URI: http://ebooks.manu2sent.com/id/eprint/2383

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