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

Samuel Philip Nobs, Aleksandra A. Kolodziejczyk, Lital Adler, Nir Horesh, Christine Botscharnikow, Ella Herzog, Gayatree Mohapatra, Sophia Hejndorf, Ryan-James Hodgetts, Igor Spivak, Lena Schorr, Leviel Fluhr, Denise Kviatcovsky, Anish Zacharia, Suzanne Njuki, Dinorah Barasch, Noa Stettner, Mally Dori-Bachash, Alon Harmelin, Alexander Brandis, Tevie Mehlman, Ayelet Erez, Yiming He, Sara Ferrini, Jens Puschhof, Hagit Shapiro, Manfred Kopf, Arieh Moussaieff, Suhaib K. Abdeen () and Eran Elinav ()
Additional contact information
Samuel Philip Nobs: Weizmann Institute of Science
Aleksandra A. Kolodziejczyk: Weizmann Institute of Science
Lital Adler: Weizmann Institute of Science
Nir Horesh: Weizmann Institute of Science
Christine Botscharnikow: Weizmann Institute of Science
Ella Herzog: Weizmann Institute of Science
Gayatree Mohapatra: Weizmann Institute of Science
Sophia Hejndorf: Weizmann Institute of Science
Ryan-James Hodgetts: Weizmann Institute of Science
Igor Spivak: Weizmann Institute of Science
Lena Schorr: DKFZ
Leviel Fluhr: Weizmann Institute of Science
Denise Kviatcovsky: Weizmann Institute of Science
Anish Zacharia: Hebrew University of Jerusalem
Suzanne Njuki: Hebrew University of Jerusalem
Dinorah Barasch: Hebrew University of Jerusalem
Noa Stettner: Weizmann Institute of Science
Mally Dori-Bachash: Weizmann Institute of Science
Alon Harmelin: Weizmann Institute of Science
Alexander Brandis: Weizmann Institute of Science
Tevie Mehlman: Weizmann Institute of Science
Ayelet Erez: Weizmann Institute of Science
Yiming He: Weizmann Institute of Science
Sara Ferrini: Weizmann Institute of Science
Jens Puschhof: DKFZ
Hagit Shapiro: Weizmann Institute of Science
Manfred Kopf: ETH Zurich
Arieh Moussaieff: Hebrew University of Jerusalem
Suhaib K. Abdeen: Weizmann Institute of Science
Eran Elinav: Weizmann Institute of Science

Nature, 2023, vol. 624, issue 7992, 645-652

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06803-0

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