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; Eran Elinav

doi:10.1038/s41586-023-06803-0

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 journal › Article › peer-review

6 Citations (Scopus)

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 language	English
Pages (from-to)	645-652
Number of pages	8
Journal	Nature
Volume	624
Issue number	7992
DOIs	https://doi.org/10.1038/s41586-023-06803-0
Publication status	Published - 21 Dec 2023

Bibliographical note

We thank the members of the Elinav lab, Weizmann Institute of Science, and members of the microbiome and cancer division, German Cancer Research Center (DKFZ), for insightful discussions. We thank the EFSD/Lilly European Diabetes Research Programme for supporting key aspects of this research. We thank E. Selzer for providing Pdk2/3/4-deficient mice; Y. Merbl for providing OT-I and OT-II mice; I. Sagi for providing PR8 influenza virus; and N. Garbi and R. Alon for providing OVA(SIINFEKL)-PR8 virus. Schemes in Supplementary Fig. were created with a licensed version of BioRender. S.P.N was supported by an SNSF Postdoc Mobility fellowship, SNSF Early Postdoc Mobility Fellowship, EMBO Long-term Fellowship no. 2017-767 and a fellowship from the Swiss Friends of the Weizmann Institute of Science. A.A.K. is a recipient of EMBO Long-term Fellowship no. 2016‐1088 and the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska‐Curie grant agreement no. 747114. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. I.S. is supported by DFG (no. SP1902/1-1). H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. L.S., J.P. and E.E. are supported by a grant from the Hector foundation. E.E. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Malka Moskowitz, Estate of Myron H. Ackerman, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kröener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research, A. Moussaieff, M. de Botton, Vainboim family, A. Davidoff, the V. R. Schwartz Research Fellow Chair and by grants funded by the European Research Council, European Union Horizon Programme, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn’s and Colitis Organization, Kenneth Rainin Foundation, Charlie Teo Foundation, CueALZ, Lupus Research Alliance, Jose Carreras Foundation, Mark Foundation for Cancer Research, Deutsch-Israelische Projektkooperation, IDSA Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).
Publisher Copyright:
© 2023, The Author(s).

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1038/s41586-023-06803-0Licence: CC BY

Cite this

Nobs, S. P., Kolodziejczyk, A. A., Adler, L., Horesh, N., Botscharnikow, C., Herzog, E., Mohapatra, G., Hejndorf, S., Hodgetts, R. J., Spivak, I., Schorr, L., Fluhr, L., Kviatcovsky, D., Zacharia, A., Njuki, S., Barasch, D., Stettner, N., Dori-Bachash, M., Harmelin, A., ... Elinav, E. (2023). Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes. Nature, 624(7992), 645-652. https://doi.org/10.1038/s41586-023-06803-0

@article{6035b36630e54be18e32aa82a50c3f3f,

title = "Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes",

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.",

author = "Nobs, {Samuel Philip} and Kolodziejczyk, {Aleksandra A.} and Lital Adler and Nir Horesh and Christine Botscharnikow and Ella Herzog and Gayatree Mohapatra and Sophia Hejndorf and Hodgetts, {Ryan James} and Igor Spivak and Lena Schorr and Leviel Fluhr and Denise Kviatcovsky and Anish Zacharia and Suzanne Njuki and Dinorah Barasch and Noa Stettner and Mally Dori-Bachash and Alon Harmelin and Alexander Brandis and Tevie Mehlman and Ayelet Erez and Yiming He and Sara Ferrini and Jens Puschhof and Hagit Shapiro and Manfred Kopf and Arieh Moussaieff and Abdeen, {Suhaib K.} and Eran Elinav",

note = "We thank the members of the Elinav lab, Weizmann Institute of Science, and members of the microbiome and cancer division, German Cancer Research Center (DKFZ), for insightful discussions. We thank the EFSD/Lilly European Diabetes Research Programme for supporting key aspects of this research. We thank E. Selzer for providing Pdk2/3/4-deficient mice; Y. Merbl for providing OT-I and OT-II mice; I. Sagi for providing PR8 influenza virus; and N. Garbi and R. Alon for providing OVA(SIINFEKL)-PR8 virus. Schemes in Supplementary Fig. were created with a licensed version of BioRender. S.P.N was supported by an SNSF Postdoc Mobility fellowship, SNSF Early Postdoc Mobility Fellowship, EMBO Long-term Fellowship no. 2017-767 and a fellowship from the Swiss Friends of the Weizmann Institute of Science. A.A.K. is a recipient of EMBO Long-term Fellowship no. 2016‐1088 and the European Union{\textquoteright}s Horizon 2020 research and innovation programme under Marie Sklodowska‐Curie grant agreement no. 747114. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. I.S. is supported by DFG (no. SP1902/1-1). H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. L.S., J.P. and E.E. are supported by a grant from the Hector foundation. E.E. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Malka Moskowitz, Estate of Myron H. Ackerman, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kr{\"o}ener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research, A. Moussaieff, M. de Botton, Vainboim family, A. Davidoff, the V. R. Schwartz Research Fellow Chair and by grants funded by the European Research Council, European Union Horizon Programme, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn{\textquoteright}s and Colitis Organization, Kenneth Rainin Foundation, Charlie Teo Foundation, CueALZ, Lupus Research Alliance, Jose Carreras Foundation, Mark Foundation for Cancer Research, Deutsch-Israelische Projektkooperation, IDSA Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

day = "21",

doi = "10.1038/s41586-023-06803-0",

language = "English",

volume = "624",

pages = "645--652",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7992",

}

Nobs, SP, Kolodziejczyk, AA, Adler, L, Horesh, N, Botscharnikow, C, Herzog, E , Mohapatra, G, Hejndorf, S, Hodgetts, RJ, Spivak, I, Schorr, L, Fluhr, L, Kviatcovsky, D, Zacharia, A, Njuki, S, Barasch, D, Stettner, N, Dori-Bachash, M, Harmelin, A , Brandis, A, Mehlman, T, Erez, A, He, Y, Ferrini, S, Puschhof, J, Shapiro, H, Kopf, M, Moussaieff, A, Abdeen, SK & Elinav, E 2023, 'Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes', Nature, vol. 624, no. 7992, pp. 645-652. https://doi.org/10.1038/s41586-023-06803-0

TY - JOUR

T1 - Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes

AU - Nobs, Samuel Philip

AU - Kolodziejczyk, Aleksandra A.

AU - Adler, Lital

AU - Horesh, Nir

AU - Botscharnikow, Christine

AU - Herzog, Ella

AU - Mohapatra, Gayatree

AU - Hejndorf, Sophia

AU - Hodgetts, Ryan James

AU - Spivak, Igor

AU - Schorr, Lena

AU - Fluhr, Leviel

AU - Kviatcovsky, Denise

AU - Zacharia, Anish

AU - Njuki, Suzanne

AU - Barasch, Dinorah

AU - Stettner, Noa

AU - Dori-Bachash, Mally

AU - Harmelin, Alon

AU - Brandis, Alexander

AU - Mehlman, Tevie

AU - Erez, Ayelet

AU - He, Yiming

AU - Ferrini, Sara

AU - Puschhof, Jens

AU - Shapiro, Hagit

AU - Kopf, Manfred

AU - Moussaieff, Arieh

AU - Abdeen, Suhaib K.

AU - Elinav, Eran

N1 - We thank the members of the Elinav lab, Weizmann Institute of Science, and members of the microbiome and cancer division, German Cancer Research Center (DKFZ), for insightful discussions. We thank the EFSD/Lilly European Diabetes Research Programme for supporting key aspects of this research. We thank E. Selzer for providing Pdk2/3/4-deficient mice; Y. Merbl for providing OT-I and OT-II mice; I. Sagi for providing PR8 influenza virus; and N. Garbi and R. Alon for providing OVA(SIINFEKL)-PR8 virus. Schemes in Supplementary Fig. were created with a licensed version of BioRender. S.P.N was supported by an SNSF Postdoc Mobility fellowship, SNSF Early Postdoc Mobility Fellowship, EMBO Long-term Fellowship no. 2017-767 and a fellowship from the Swiss Friends of the Weizmann Institute of Science. A.A.K. is a recipient of EMBO Long-term Fellowship no. 2016‐1088 and the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska‐Curie grant agreement no. 747114. S.K.A. is supported by the Israeli Ministry of Science and Technology Zvi Yanai Fellowship. I.S. is supported by DFG (no. SP1902/1-1). H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. L.S., J.P. and E.E. are supported by a grant from the Hector foundation. E.E. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, Adelis Foundation, Pearl Welinsky Merlo Scientific Progress Research Fund, Park Avenue Charitable Fund, Hanna and Dr Ludwik Wallach Cancer Research Fund, Daniel Morris Trust, Wolfson Family Charitable Trust and Wolfson Foundation, Ben B. and Joyce E. Eisenberg Foundation, White Rose International Foundation, Estate of Malka Moskowitz, Estate of Myron H. Ackerman, Estate of Bernard Bishin for the WIS-Clalit Program, Else Kröener-Fresenius Foundation, Jeanne and Joseph Nissim Center for Life Sciences Research, A. Moussaieff, M. de Botton, Vainboim family, A. Davidoff, the V. R. Schwartz Research Fellow Chair and by grants funded by the European Research Council, European Union Horizon Programme, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn’s and Colitis Organization, Kenneth Rainin Foundation, Charlie Teo Foundation, CueALZ, Lupus Research Alliance, Jose Carreras Foundation, Mark Foundation for Cancer Research, Deutsch-Israelische Projektkooperation, IDSA Foundation and Wellcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12/21

Y1 - 2023/12/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85179302290&partnerID=8YFLogxK

U2 - 10.1038/s41586-023-06803-0

DO - 10.1038/s41586-023-06803-0

M3 - Article

AN - SCOPUS:85179302290

SN - 0028-0836

VL - 624

SP - 645

EP - 652

JO - Nature

JF - Nature

IS - 7992

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this