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An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

View ORCID ProfileReuben McGregor, View ORCID ProfileDaniel Chauss, View ORCID ProfileTilo Freiwald, View ORCID ProfileBingyu Yan, View ORCID ProfileLuopin Wang, View ORCID ProfileEstefania Nova-Lamperti, Zonghao Zhang, Heather Teague, Erin E West, View ORCID ProfileJack Bibby, Audrey Kelly, Amna Malik, Alexandra F Freeman, View ORCID ProfileDaniella Schwartz, Didier Portilla, View ORCID ProfileSusan John, Paul Lavender, View ORCID ProfileMichail S Lionakis, View ORCID ProfileNehal N Mehta, View ORCID ProfileClaudia Kemper, View ORCID ProfileNichola Cooper, View ORCID ProfileGiovanna Lombardi, View ORCID ProfileArian Laurence, View ORCID ProfileMajid Kazemian, View ORCID ProfileBehdad Afzali
doi: https://doi.org/10.1101/2020.07.18.210161
Reuben McGregor
1Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
2Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand
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Daniel Chauss
1Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
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Tilo Freiwald
1Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
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Bingyu Yan
3Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
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Luopin Wang
3Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
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Estefania Nova-Lamperti
4Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy; Universidad de Concepcion, Concepcion, Chile
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Zonghao Zhang
5Department of Agricultural and Biological Engineering, Purdue University, West Lafayette IN, USA
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Heather Teague
6Laboratory of Inflammation & Cardiometabolic diseases, Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
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Erin E West
7Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
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Jack Bibby
7Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
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Audrey Kelly
8School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Amna Malik
9Department of Medicine, Imperial College London, London, UK
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Alexandra F Freeman
10Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
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Daniella Schwartz
11Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
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Didier Portilla
1Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
12Division of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, VA, USA
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Susan John
8School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Paul Lavender
8School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Michail S Lionakis
13Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
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Nehal N Mehta
6Laboratory of Inflammation & Cardiometabolic diseases, Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
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Claudia Kemper
7Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
14Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
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Nichola Cooper
9Department of Medicine, Imperial College London, London, UK
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Giovanna Lombardi
15MRC Centre for Transplantation, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Arian Laurence
16Nuffield Department of Medicine, University of Oxford, UK
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Majid Kazemian
3Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
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  • For correspondence: kazemian@purdue.edu behdad.afzali@nih.gov
Behdad Afzali
1Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA
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  • For correspondence: kazemian@purdue.edu behdad.afzali@nih.gov
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Abstract

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner1,2. Excessive complement and IFN-γ-associated responses are known drivers of immunopathogenesis3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection4. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-γ producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-γ+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor5–7. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† Joint first *Joint last authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted July 19, 2020.
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An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19
Reuben McGregor, Daniel Chauss, Tilo Freiwald, Bingyu Yan, Luopin Wang, Estefania Nova-Lamperti, Zonghao Zhang, Heather Teague, Erin E West, Jack Bibby, Audrey Kelly, Amna Malik, Alexandra F Freeman, Daniella Schwartz, Didier Portilla, Susan John, Paul Lavender, Michail S Lionakis, Nehal N Mehta, Claudia Kemper, Nichola Cooper, Giovanna Lombardi, Arian Laurence, Majid Kazemian, Behdad Afzali
bioRxiv 2020.07.18.210161; doi: https://doi.org/10.1101/2020.07.18.210161
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An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19
Reuben McGregor, Daniel Chauss, Tilo Freiwald, Bingyu Yan, Luopin Wang, Estefania Nova-Lamperti, Zonghao Zhang, Heather Teague, Erin E West, Jack Bibby, Audrey Kelly, Amna Malik, Alexandra F Freeman, Daniella Schwartz, Didier Portilla, Susan John, Paul Lavender, Michail S Lionakis, Nehal N Mehta, Claudia Kemper, Nichola Cooper, Giovanna Lombardi, Arian Laurence, Majid Kazemian, Behdad Afzali
bioRxiv 2020.07.18.210161; doi: https://doi.org/10.1101/2020.07.18.210161

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