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

ABSTRACT: Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyzed the transcriptomes of 605,904 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 observed a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD epithelial cells expressed higher levels of genes linked directly to the efficiency of viral replication and innate immune response. Additionally, we identified 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.

SUBMITTER: Bui LT

PROVIDER: S-EPMC7587778 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Bui Linh T LT Winters Nichelle I NI Chung Mei-I MI Joseph Chitra C Gutierrez Austin J AJ Habermann Arun C AC Adams Taylor S TS Schupp Jonas C JC Poli Sergio S Peter Lance M LM Taylor Chase J CJ Blackburn Jessica B JB Richmond Bradley W BW Nicholson Andrew G AG Rassl Doris D Wallace William A WA Rosas Ivan O IO Jenkins R Gisli RG Kaminski Naftali N Kropski Jonathan A JA Banovich Nicholas E NE

bioRxiv : the preprint server for biology 20210104

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyzed the transcriptomes of 605,904 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 observed a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD epithelial c ...[more]

PMID: 33106805

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Project description:Angiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19). COVID-19 disease severity is typically lower in pediatric patients than adults (particularly the elderly), but higher rates of hospitalizations requiring intensive care are observed in infants than in older children - the reasons for these differences are unknown. ACE2 is expressed in several adult tissues and cells, including alveolar type 2 cells of the distal lung epithelium, but expression at other ages is largely unexplored. Here we show that ACE2 transcripts are expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood. Notably, the repertoire of cells expressing ACE2 protein in the mouse lung and airways shifts during key phases of lung maturation. In particular, podoplanin-positive cells, which are likely alveolar type I cells responsible for gas exchange, express ACE2 only in advanced age. Similar patterns of expression were evident in analysis of human lung tissue from over 100 donors, along with extreme inter- and intra-individual heterogeneity in ACE2 protein expression in epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in young individuals, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells and may thus limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for translation of apoptosis modulating drugs as novel treatments for COVID-19.

Project description:BackgroundManagement of patients with respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), became challenging during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic due to infection prevention measures. To maintain care, a remote monitoring program was initiated, comprising a smartphone app and a Bluetooth spirometry device.ObjectiveTo assess patient- and physician-related experience with remote monitoring.Material and methodsStructured questionnaires were developed to rate experiences from the patient or physician perspective on six-level Likert scales. Interactions between patients and physicians via the digital platform and overall utilization was analyzed.ResultsA total of 745 patients with asthma, COPD, post-coronavirus disease 2019 (COVID-19) and other respiratory diseases were enrolled from 31 centers in Germany. Mean follow-up was 49.4 ± 12.6 weeks. Each participant submitted on average 289 measurements. Patient-reported experience with the remote monitoring program was positive, with the highest satisfaction reported for "Experience with home measurement" (1.4 ± 0.5; 99% positive), followed by "Communication/interaction" (1.8 ± 0.9; 83% positive) and "Overall satisfaction with program" (1.8 ± 0.8; 87% positive). In all, 70% reported subjective quality of life improvements related to participation in the program. Physician satisfaction with the program was also high with a mean rating of 2.2 ± 1.2.DiscussionApp-based remote monitoring was successfully implemented in routine care during the SARS-CoV‑2 pandemic and demonstrated potential for improvements in care. Patient-relevant experience was positive in all dimensions and remote monitoring was well accepted. Physicians who participated in the program also expressed positive experiences, as demonstrated by a high level of interaction with the platform and positive evaluations of effects from the program.

Dataset Information

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

Publications

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

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