Abstract

Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

Dexamethasone has been used in the treatment of critically ill COVID-19 patients. Here the authors apply transcriptomics to investigate the effects of dexamethasone treatment in COVID-19 patients, and show both systemic and compartment-specific effects.

Details

Title
Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19
Author
Neyton, Lucile P. A. 1   VIAFID ORCID Logo  ; Patel, Ravi K. 2   VIAFID ORCID Logo  ; Sarma, Aartik 1   VIAFID ORCID Logo  ; Ansel, K. Mark 3 ; Christenson, Stephanie 1 ; Adkisson, Michael 2 ; Eckalbar, Walter 4 ; Maliskova, Lenka 2 ; Schroeder, Andrew 2 ; Bueno, Raymund 5 ; Gordon, Gracie 6 ; Hartoularos, George 7 ; Kushnoor, Divya 8 ; Lee, David 5 ; McCarthy, Elizabeth 9 ; Ogorodnikov, Anton 10 ; Spitzer, Matthew 11 ; Hiam, Kamir 12 ; Song, Yun S. 13 ; Sun, Yang 5 ; Tumurbaatar, Erden 5 ; van der Wijst, Monique 14 ; Whatley, Alexander 15 ; Jones, Chayse 1 ; Caldera, Saharai 16 ; DeVoe, Catherine 16 ; Serpa, Paula Hayakawa 16 ; Love, Christina 16 ; Mick, Eran 17 ; Phelps, Maira 18 ; Tsitsiklis, Alexandra 16 ; Leroux, Carolyn 1 ; Rashid, Sadeed 19 ; Rodriguez, Nicklaus 19 ; Tang, Kevin 19 ; Altamirano, Luz Torres 19 ; Leligdowicz, Aleksandra 20 ; Matthay, Michael 21 ; Wilson, Michael 22 ; Ye, Jimmie 23 ; Chak, Suzanna 24 ; Ghale, Rajani 1 ; Jauregui, Alejandra 1 ; Lee, Deanna 25 ; Nguyen, Viet 25 ; Sigman, Austin 1 ; Kangelaris, Kirsten N. 20 ; Asthana, Saurabh 26 ; Collins, Zachary 26 ; Patel, Ravi 2 ; Rao, Arjun 26 ; Samad, Bushra 26 ; Shaw, Cole 27 ; Lea, Tasha 8 ; Ward, Alyssa 5 ; Jones, Norman 28 ; Milush, Jeff 28 ; Chan, Vincent 10 ; Chew, Nayvin 29 ; Combes, Alexis 29 ; Courau, Tristan 29 ; Hu, Kenneth 8 ; Huang, Billy 30 ; Kumar, Nitasha 28 ; Mahboob, Salman 30 ; Muñoz-Sandoval, Priscila 3 ; Parada, Randy 30 ; Reeder, Gabriella 31 ; Shen, Alan 29 ; Tsui, Jessica 29 ; Zha, Shoshana 1 ; Zhu, Wandi S. 3 ; Willmore, Andrew 1 ; Haller, Sidney C. 1 ; Eckalbar, Walter L. 32 ; Erle, David J. 33   VIAFID ORCID Logo  ; Krummel, Matthew F. 8   VIAFID ORCID Logo  ; Hendrickson, Carolyn M. 1   VIAFID ORCID Logo  ; Woodruff, Prescott G. 1 ; Langelier, Charles R. 17   VIAFID ORCID Logo  ; Calfee, Carolyn S. 34 ; Fragiadakis, Gabriela K. 35   VIAFID ORCID Logo 

1  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
2  University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
3  University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Sandler Asthma Basic Research Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
4  University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
5  University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
6  San Francisco, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco, Institute for Human Genetics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco, Biological and Medical Informatics Graduate Program, University of California, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
7  San Francisco, Biological and Medical Informatics Graduate Program, University of California, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
8  University of California, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
9  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175); University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
10  University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
11  University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco, Department of Otolaryngology, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
12  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175); University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco, Department of Otolaryngology, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Parker Institute for Cancer Immunotherapy, San Francisco, USA (GRID:grid.489192.f) (ISNI:0000 0004 7782 4884) 
13  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175); Berkeley, Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, USA (GRID:grid.47840.3f) (ISNI:0000 0001 2181 7878); Berkeley, Department of Statistics, University of California, Berkeley, USA (GRID:grid.30389.31) (ISNI:0000 0001 2348 0690) 
14  University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); San Francisco, Institute for Human Genetics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
15  Berkeley, Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, USA (GRID:grid.47840.3f) (ISNI:0000 0001 2181 7878) 
16  University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
17  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175); University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
18  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) (ISNI:0000 0004 9234 0175) 
19  University of California, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
20  University of Toronto, Department of Medicine, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
21  University of California, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Anesthesia, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); San Francisco, Cardiovascular Research Institute, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
22  University of California, Weill Institute for Neurosciences, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
23  University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); San Francisco, Institute for Human Genetics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Epidemiology and Biostatistics, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Institute of Computational Health Sciences, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
24  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of Toronto, Department of Medicine, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
25  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); San Francisco, Cardiovascular Research Institute, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
26  University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
27  University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
28  University of California, Core Immunology Laboratory, Division of Experimental Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
29  University of California, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California, Department of Anatomy, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Disease 2 Biology CoLab, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
30  University of California, Department of Orofacial Sciences, School of Dentistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
31  University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California, Disease 2 Biology CoLab, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California, Biomedical Sciences Graduate Program, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
32  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
33  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Lung Biology Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
34  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046); University of California, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Anesthesia, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
35  University of California San Francisco, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.468726.9) (ISNI:0000 0004 0486 2046) 
Pages
5483
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-49756-2
ProQuest document ID
3073444979
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.