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      Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

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          Abstract

          Zoonotically transmitted coronaviruses are responsible for three disease outbreaks since 2002, including the current COVID-19 pandemic, caused by SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the receptor for SARS-CoV-2. Despite numerous reports describing ACE2 mRNA abundance and tissue distribution, there remains a paucity of data evaluating ACE2 protein and its correlation with other SARS-CoV-2 susceptibility factors. Here, we systematically examined the human upper and lower respiratory tract using single-cell RNA sequencing and immunohistochemistry to determine receptor expression and evaluated its association with risk factors for severe COVID-19. Our results reveal that ACE2 protein is highest within the sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe disease development, respectively. In the lung parenchyma, ACE2 protein was found on the apical surface of a small subset of alveolar type II cells and colocalized with TMPRSS2, a cofactor for SARS-CoV2 entry. ACE2 protein was not increased by pulmonary risk factors for severe COVID-19. However, ACE2 protein was increased in children, a demographic with a reduced incidence of severe COVID-19. These results offer new insights into ACE2 localization and function in susceptibility to COVID-19.

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          Most cited references 13

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          Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis

          Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
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            Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor

            The angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for the severe acute respiratory syndrome associated coronavirus (SARS-CoV). Here we show that ACE2 expression on cell lines correlates with susceptibility to SARS-CoV S-driven infection, suggesting that ACE2 is a major receptor for SARS-CoV. The soluble ectodomain of ACE2 specifically abrogated S-mediated infection and might therefore be exploited for the generation of inhibitors. Deletion of a major portion of the cytoplasmic domain of ACE2 had no effect on S-driven infection, indicating that this domain is not important for receptor function. Our results point to a central role of ACE2 in SARS-CoV infection and suggest a minor contribution of the cytoplasmic domain to receptor function.
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              Coronavirus disease (COVID‐19) and neonate: What neonatologist need to know

               Qi Lu,  Yuan Shi (2020)
              Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) cause china epidemics with high morbidity and mortality, the infection has been transmitted to other countries. About three neonates and more than 230 children cases are reported. The disease condition of the main children was mild. There is currently no evidence that SARS‐CoV‐2 can be transmitted transplacentally from mother to the newborn. The treatment strategy for children with Coronavirus disease (COVID‐19) is based on adult experience. Thus far, no deaths have been reported in the pediatric age group. This review describes the current understanding of COVID‐19 infection in newborns and children.
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                Author and article information

                Journal
                bioRxiv
                BIORXIV
                bioRxiv
                Cold Spring Harbor Laboratory
                01 June 2020
                Affiliations
                [1 ]Department of Pediatrics, University of Iowa College of Medicine, University of Iowa, Iowa City, IA USA
                [2 ]Department of Internal Medicine, University of Iowa College of Medicine, University of Iowa, Iowa City, IA USA
                [3 ]Department of Pathology, University of Iowa College of Medicine, University of Iowa, Iowa City, IA USA
                Author notes
                [*]

                Contributed equally

                Author contributions:

                Conceptualization and writing – original draft, M.O.B., P.B.M. and D.K.M.; Data curation, A.T.; Formal analysis, M.O.B., A.T., A.P. and D.K.M.; Investigation, A.T., A.P., M.R.L., C.W.-L. and D.K.M.; Visualization, M.O.B., A.T., D.K.M.; Resources, A.P., J.A.K.-T., P.H.K., P.T., P.B.M. and D.K.M.; Writing – review and editing, M.O.B, A.T., A.P., M.R.L., J.A.K.-T., P.H.K., P.T., C.W.-L., P.B.M. and D.K.M

                Correspondence: David K. Meyerholz ( david-meyerholz@ 123456uiowa.edu ), Paul B. McCray, Jr. ( paul-mccray@ 123456uiowa.edu )
                Article
                10.1101/2020.04.22.056127
                7302220
                32577664

                It is made available under a CC-BY-ND 4.0 International license.

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