Abstract

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a “cytokine storm,” we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.

Here, the authors perform transcriptional profiling on tracheal aspirates of adults requiring mechanical ventilation for SARS-CoV2-induced acute respiratory distress syndrome (ARDS) and identify a dysregulated host response predicted to predicted to be potentially modulated by dexamethasone.

Details

Title
Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS
Author
Sarma Aartik 1   VIAFID ORCID Logo  ; Christenson, Stephanie A 1 ; Byrne, Ashley 2   VIAFID ORCID Logo  ; Mick Eran 3   VIAFID ORCID Logo  ; Pisco Angela Oliveira 2   VIAFID ORCID Logo  ; DeVoe, Catherine 4 ; Deiss, Thomas 2 ; Ghale Rajani 5 ; Zha, Beth Shoshana 1 ; Tsitsiklis Alexandra 4   VIAFID ORCID Logo  ; Jauregui Alejandra 1 ; Moazed Farzad 1 ; Detweiler, Angela M 4 ; Spottiswoode Natasha 6 ; Sinha Pratik 7 ; Neff, Norma 2   VIAFID ORCID Logo  ; Tan, Michelle 2 ; Serpa Paula Hayakawa 4 ; Willmore, Andrew 1 ; Mark, Ansel K 8   VIAFID ORCID Logo  ; Wilson, Jennifer G 9 ; Leligdowicz Aleksandra 10 ; Siegel, Emily R 11 ; Sirota, Marina 12 ; DeRisi, Joseph L 13 ; Matthay, Michael A 14   VIAFID ORCID Logo  ; Abe-Jones, Yumiko 15 ; Asthana Saurabh 16 ; Beagle, Alexander 6 ; Bhakta Tanvi 17 ; Bhide Sharvari 1 ; Cai, Cathy 18 ; Caldera Saharai 4 ; Calfee, Carolyn 14 ; Calvo, Maria 1 ; Carrillo, Sidney 1 ; Adithya, Cattamanchi 1 ; Chak Suzanna 1 ; Chan, Vincent 19 ; Chew Nayvin 20 ; Christenson, Stephanie 1 ; Collins, Zachary 16 ; Combes, Alexis 20 ; Courau Tristan 20 ; Darmanis Spyros 21 ; Erle, David 22 ; Esmaili Armond 15 ; Fragiadakis, Gabriela K 23 ; Giberson, Jeremy 1 ; Gonzalez, Ana 1 ; Hendrickson, Carolyn 1 ; Kamir, Hiam 24 ; Hu, Kenneth 25 ; Huang, Billy 26 ; Jones Chayse 1 ; Jones, Norman 27 ; Kangelaris Kirsten 6 ; Krummel, Matthew 28 ; Kumar, Nitasha 27 ; Kushnoor Divya 20 ; Lea Tasha 25 ; Lee, Deanna 29 ; Lee, David 12 ; Liu, Kathleen D 30 ; Liu, Yale 31 ; Mahboob Salman 26 ; Matthay, Michael 14 ; Milush Jeff 27 ; Muñoz-Sandoval Priscila 8 ; Nguyen, Viet 29 ; Ortiz, Gabe 32 ; Parada, Randy 26 ; Phelps Maira 2 ; Pierce, Logan 15 ; Prasad Priya 15 ; Rao, Arjun 16 ; Rashid Sadeed 33 ; Reeder, Gabriella 34 ; Rodriguez Nicklaus 33 ; Samad Bushra 16 ; Scarlet Diane 35 ; Shaw, Cole 36 ; Shen, Alan 20 ; Sigman, Austin 1 ; Spitzer, Matthew 24 ; Sun, Yang 12 ; Sunshine, Sara 37 ; Tang, Kevin 33 ; Altamirano Luz Torres 33 ; Tsui, Jessica 20 ; Tumurbaatar Erden 12 ; Turner, Kathleen 38 ; Ward, Alyssa 12 ; Wilson, Michael 39 ; Winkler Juliane 40 ; Withers Reese 38 ; Wong, Kristine 18 ; Woodruff Prescott 41 ; Ye, Jimmie 42 ; Yee, Kimberly 1 ; Yu, Michelle 1 ; Zha Shoshana 1 ; Zhan, Jenny 18 ; Zhou Mingyue 18 ; Zhu, Wandi S 8 ; Hendrickson, Carolyn M 1 ; Kangelaris, Kirsten N 6 ; Krummel, Matthew F 25 ; Woodruff, Prescott G 41 ; Erle, David J 43   VIAFID ORCID Logo  ; Calfee, Carolyn S 14 ; Langelier, Charles R 44   VIAFID ORCID Logo 

1  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
2  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a) 
3  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a); University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
4  University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
5  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
6  University of California, Department of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
7  Washington University, Department of Anesthesia, Saint Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
8  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) 
9  Stanford University, Department of Emergency Medicine, Palo Alto, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
10  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of California, Cardiovascular Research Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
11  University of California, School of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
12  University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
13  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a); University of California, Department of Biochemistry and Biophysics, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
14  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Cardiovascular Research Institute, 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) 
15  University of California, Division of Hospital Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
16  University of California, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Data Science CoLab, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
17  Zuckerberg San Francisco General Hospital and Trauma Center, Department of Nursing, San Francisco, USA (GRID:grid.416732.5) (ISNI:0000 0001 2348 2960) 
18  University of California, Biospecimen Resource Program, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
19  University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
20  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.266102.1) (ISNI:0000 0001 2297 6811); 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.266102.1) (ISNI:0000 0001 2297 6811) 
21  Genentech Inc, Microchemistry, Proteomics and Lipidomics Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
22  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, 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); University of California, CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
23  University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
24  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a); University of California, Department of Microbiology and Immunology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Otolaryngology, 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); Parker Institute for Cancer Immunotherapy, San Francisco, USA (GRID:grid.489192.f) 
25  University of California, Department of Pathology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
26  University of California, Department of Orofacial Sciences, School of Dentistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
27  University of California, Core Immunology Laboratory, Division of Experimental Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
28  University of California, ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Departments of Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
29  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Cardiovascular Research Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
30  University of California San Francisco, Division of Nephrology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Division of Critical Care Medicine, Department of Anesthesia, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
31  University of California, Department of Dermatology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
32  University of California, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
33  University of California, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
34  University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Disease 2 Biology CoLab, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Biomedical Sciences Graduate Program, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
35  Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, USA (GRID:grid.416732.5) (ISNI:0000 0001 2348 2960) 
36  University of California, Data Science CoLab, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, Bakar ImmunoX Initiative, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California, CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
37  University of California, Department of Biochemistry and Biophysics, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
38  University of California, Department of Nursing, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
39  University of California, Weill Institute for Neurosciences, Department of Neurology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
40  University of California, School of Dentistry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
41  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, 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) 
42  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a); University of California, Division of Rheumatology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Parker Institute for Cancer Immunotherapy, San Francisco, USA (GRID:grid.489192.f); University of California, Institute for Human Genetics, 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) 
43  University of California, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, 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); University of California, UCSF CoLabs, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
44  Chan Zuckerberg Biohub, San Francisco, USA (GRID:grid.499295.a); University of California, Division of Infectious Diseases, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-25040-5
ProQuest document ID
2564699950
Copyright
© The Author(s) 2021. 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.