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Dev Cell ; 57(1): 112-145.e2, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1587971


The human lung plays vital roles in respiration, host defense, and basic physiology. Recent technological advancements such as single-cell RNA sequencing and genetic lineage tracing have revealed novel cell types and enriched functional properties of existing cell types in lung. The time has come to take a new census. Initiated by members of the NHLBI-funded LungMAP Consortium and aided by experts in the lung biology community, we synthesized current data into a comprehensive and practical cellular census of the lung. Identities of cell types in the normal lung are captured in individual cell cards with delineation of function, markers, developmental lineages, heterogeneity, regenerative potential, disease links, and key experimental tools. This publication will serve as the starting point of a live, up-to-date guide for lung research at We hope that Lung CellCards will promote the community-wide effort to establish, maintain, and restore respiratory health.

Lung/cytology , Lung/physiology , Cell Differentiation/genetics , Databases as Topic , Humans , Lung/metabolism , Regeneration/genetics , Single-Cell Analysis/methods
Elife ; 92020 11 09.
Article in English | MEDLINE | ID: covidwho-969888


Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.

COVID-19/genetics , COVID-19/virology , Host Microbial Interactions/genetics , Lung/metabolism , Lung/virology , Adult , Age Factors , Alveolar Epithelial Cells/classification , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Child, Preschool , Chromosome Mapping , Gene Expression Profiling , Genetic Variation , Host Microbial Interactions/physiology , Humans , Infant, Newborn , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Pandemics , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Single-Cell Analysis , Virus Internalization
Am J Physiol Lung Cell Mol Physiol ; 319(4): L670-L674, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-798131


The severity of coronavirus disease 2019 (COVID-19) is linked to an increasing number of risk factors, including exogenous (environmental) stimuli such as air pollution, nicotine, and cigarette smoke. These three factors increase the expression of angiotensin I converting enzyme 2 (ACE2), a key receptor involved in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the etiological agent of COVID-19-into respiratory tract epithelial cells. Patients with severe COVID-19 are managed with oxygen support, as are at-risk individuals with chronic lung disease. To date, no study has examined whether an increased fraction of inspired oxygen (FiO2) may affect the expression of SARS-CoV-2 entry receptors and co-receptors, including ACE2 and the transmembrane serine proteases TMPRSS1, TMPRSS2, and TMPRSS11D. To address this, steady-state mRNA levels for genes encoding these SARS-CoV-2 receptors were assessed in the lungs of mouse pups chronically exposed to elevated FiO2, and in the lungs of preterm-born human infants chronically managed with an elevated FiO2. These two scenarios served as models of chronic elevated FiO2 exposure. Additionally, SARS-CoV-2 receptor expression was assessed in primary human nasal, tracheal, esophageal, bronchial, and alveolar epithelial cells, as well as primary mouse alveolar type II cells exposed to elevated oxygen concentrations. While gene expression of ACE2 was unaffected, gene and protein expression of TMPRSS11D was consistently upregulated by exposure to an elevated FiO2. These data highlight the need for further studies that examine the relative contribution of the various viral co-receptors on the infection cycle, and point to oxygen supplementation as a potential risk factor for COVID-19.

Coronavirus Infections/pathology , Membrane Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Respiratory Mucosa/metabolism , Serine Endopeptidases/metabolism , Serine Proteases/metabolism , Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Cells, Cultured , Female , Humans , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Oxygen/administration & dosage , Oxygen/analysis , Pandemics , Receptors, Virus/metabolism , Risk Factors , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Proteases/genetics , Severity of Illness Index