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 BrandisTevie Mehlman, Ayelet Erez, Yiming He, Sara Ferrini, Jens Puschhof, Hagit Shapiro, Manfred Kopf, Arieh Moussaieff, Suhaib K. Abdeen*, Eran Elinav*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageAmerican English
Pages (from-to)645-652
Number of pages8
JournalNature
Volume624
Issue number7992
DOIs
StatePublished - 21 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

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