Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

Linh Bui ,Jeffrey A Whitsett ,Chase J Taylor ,Jessica B Blackburn ,Doris M Rassl ,Naftali Kaminski ,Aviv Regev ,Kourosh Saeb‐Parsy ,Joachim L Schultze ,Péter Horváth ,Tommaso Biancalani ,Jiyeon Choi ,Andrew G Nicholson ,Oliver Eickelberg ,Taylor Adams ,Nichelle I Winters ,Haeock Lee ,Douglas P Shepherd ,Jonas C Schupp ,Sylvie Leroy ,Joakim Lundeberg ,José Ordovás-Montañés ,Alex K Shalek ,Herbert B Schiller ,Avrum Spira ,Jayaraj Rajagopal ,Emma L Rawlins ,Joseph E Powell ,Marko Nikolić ,Tushar J Desai ,Jonathan A Kropski ,Iván O Rosas ,Purushothama Rao Tata ,Maarten Van Den Berge ,Mauricio Rojas ,Lance Peter ,Jennifer Griffonnet ,Martijn C Nawijn ,Orit Rosenblatt-Rosen ,William Wallace ,Sarah A Teichmann ,Max A Seibold ,Mei-I Chung ,Charles‐Hugo Marquette ,Austin J Gutierrez ,Kun Zhang ,Arun C Habermann ,Paul Hofman ,Pascal Barbry ,Alexander V Misharin ,Paul A Reyfman ,Muzlifah Haniffa ,Xin Sun ,Fabian J Theis ,Chitra Joseph ,Mark A Krasnow ,Malte Kühnemund ,Thao Duong ,Dana Pe’er ,Robert Lafyatis ,Sergio Poli ,Alvis Brāzma ,Jason R Spence ,Alexander Tsankov ,Gisli Jenkins ,Nicholas E Banovich ,Michael Von Papen ,Christos Samakovlis ,Stephen R Quake ,Kerstin B Meyer ,Bradley W Richmond ,Laure‐Emmanuelle Zaragosi

doi:10.1038/s41467-021-24467-0

Abstract

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.

Highlights

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes
We found that CLD is associated with baseline changes in cell-type specific expression of genes related to viral replication and the immune response, as well as evidence of immune exhaustion and altered inflammatory gene expression
We analyzed the transcriptomes from 611,398 single cells derived from healthy donors (78 samples), chronic obstructive pulmonary disease (COPD) (31 samples), Idiopathic Pulmonary Fibrosis (IPF) (82 samples) and Non-IPF interstitial lung disease (ILDs) (Other ILD, 19 samples) (Supplementary Table 1b, 2)

Summary

Introduction

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. We performed an integrated analysis of four lung single cell RNA-sequencing (scRNA-seq) datasets[29,30,31,32] in addition to unpublished data, together including 78 control and 132 CLD samples (n = 31 COPD, 82 IPF and 19 other ILDs), to investigate the molecular basis of SARS-CoV-2 severity and mortality risk in CLD patients. We found that CLD is associated with baseline changes in cell-type specific expression of genes related to viral replication and the immune response, as well as evidence of immune exhaustion and altered inflammatory gene expression Together, these data provide a molecular framework underlying the increased risk of SARS-CoV-2 severity and poor outcomes in patients with certain pre-existing CLD

Methods

Results

Conclusion