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    Fibrinolysis influences SARS-CoV-2 infection MESHD in ciliated cells

    Authors: Myoung Ryoul Park; Chunmei Cai; Min-Jung Seo; Hong-Tae Yun; Soo-Kwon Park; Man-Soo Choi; Chang-Hwan Park; Jung Kyung Moon

    doi:10.1101/2021.01.07.425801 Date: 2021-01-08 Source: bioRxiv

    Rapid spread of COVID-19 MESHD has caused an unprecedented pandemic worldwide, and an inserted furin HGNC site in SARS-CoV-2 spike PROTEIN protein (S PROTEIN) may account for increased transmissibility. Plasmin HGNC, and other host proteases, may cleave the furin HGNC site of SARS-CoV-2 S protein PROTEIN and {gamma} subunits of epithelial sodium channels ({gamma} ENaC), resulting in an increment in virus infectivity and channel activity. As for the importance of ENaC in the regulation of airway surface and alveolar fluid homeostasis MESHD, whether SARS-CoV-2 will share and strengthen the cleavage network with ENaC proteins at the single-cell level is urgently worthy of consideration. To address this issue, we analyzed single-cell RNA sequence (scRNA-seq) datasets, and found the PLAU HGNC (encoding urokinase plasminogen activator), SCNN1G HGNC ({gamma}ENaC), and ACE2 HGNC (SARS-CoV-2 receptor) were co-expressed in alveolar epithelial MESHD, basal, club, and ciliated epithelial cells. The relative expression level of PLAU HGNC, TMPRSS2 HGNC, and ACE2 HGNC were significantly upregulated in severe COVID-19 MESHD patients and SARS-CoV-2 infected MESHD cell lines using Seurat and DESeq2 R packages. Moreover, the increments in PLAU HGNC, FURIN HGNC, TMPRSS2 HGNC, and ACE2 HGNC were predominately observed in different epithelial cells and leukocytes. Accordingly, SARS-CoV-2 may share and strengthen the ENaC fibrinolytic proteases network in ACE2 HGNC positive airway and alveolar MESHD epithelial cells, which may expedite virus infusion into the susceptible cells and bring about ENaC associated edematous respiratory condition MESHD.

    Paradoxical effects of cigarette smoke and COPD MESHD on SARS-CoV2 infection MESHD and disease

    Authors: Michael Tomchaney; Marco Contoli; Jonathan Mayo; Simonetta Baraldo; Shuaizhi Li; Carly Cabel; David Bull; Scott Lick; Joshua Malo; Steve Knoper; Samuel Kim; Judy Tram; Joselyn Rojas Quintero; Monica Kraft; Julie Ledford; Fernando D Martinez; Curtis Thorne; Farrah Kheradmand; Samuel K Campos; Alberto Papi; Francesca Polverino

    doi:10.1101/2020.12.07.413252 Date: 2020-12-07 Source: bioRxiv

    IntroductionHow cigarette smoke (CS) and chronic obstructive pulmonary disease MESHD ( COPD MESHD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD and severity is controversial. We investigated the protein and mRNA expression of SARS-CoV-2 entry receptor ACE2 HGNC and proteinase TMPRSS2 HGNC in lungs from COPD MESHD patients and controls, and lung tissue from mice exposed acutely and chronically to CS. Also, we investigated the effects of CS exposure on SARS-CoV-2 infection MESHD in human bronchial epithelial cells. MethodsIn Cohort 1, ACE2 HGNC-positive cells were quantified by immunostaining in FFPE sections from both central and peripheral airways. In Cohort 2, we quantified pulmonary ACE2 HGNC protein levels by immunostaining and ELISA, and both ACE2 HGNC and TMPRSS2 HGNC mRNA levels by RT-qPCR. In C57BL/6 WT mice exposed to air or CS for up to 6 months, pulmonary ACE2 protein levels were quantified by triple immunofluorescence staining and ELISA. The effects of CS exposure on SARS-CoV-2 infection MESHD were evaluated after 72hr in vitro infection of Calu-3 cells. After SARS-CoV-2 infection MESHD, the cells were fixed for IF staining with dsRNA-specific J2 monoclonal Ab, and cell lysates were harvested for WB of viral nucleocapsid (N) protein PROTEIN. Supernatants (SN) and cytoplasmic lysates were obtained to measure ACE2 HGNC levels by ELISA. ResultsIn both human cohorts, ACE2 HGNC protein and mRNA levels were decreased in peripheral airways from COPD MESHD patients versus both smoker and NS controls, but similar in central airways. TMPRSS2 HGNC levels were similar across groups. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia MESHD versus air-exposed mice exposed to 3 and 6 months of CS. In Calu3 cells in vitro, CS-treatment abrogated infection to levels below the limit of detection. Similar results were seen with WB for viral N protein PROTEIN, showing peak viral protein synthesis at 72hr. ConclusionsACE2 levels were decreased in both bronchial and alveolar epithelial MESHD cells from uninfected COPD MESHD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-treatment did not affect ACE2 levels but potently inhibited SARS-CoV-2 replication in this in vitro model. These findings urge to further investigate the controversial effects of CS and COPD MESHD on SARS-CoV2 infection MESHD.

    Upregulation of ACE2 HGNC and TMPRSS2 HGNC by particulate matter and idiopathic pulmonary fibrosis: A potential role in severe COVID-19 MESHD

    Authors: Hsin-Hsien Li; Chen-Chi Liu; Tien-Wei Hsu; Jiun-Han Lin; Jyuan-Wei Hsu; Anna Fen-Yau Li; Yi-Chen Yeh; Han-Shui Hsu; Shih-Chieh Hung

    doi:10.21203/rs.3.rs-112349/v1 Date: 2020-11-20 Source: ResearchSquare

    Background: Air pollution and idiopathic pulmonary fibrosis MESHD ( IPF MESHD) cause a poor prognosis after COVID-19 MESHD infection, but the underlying mechanisms are not well exploited. Angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) and transmembrane serine protease 2 ( TMPRSS2 HGNC) are the keys to the entry of SARS-CoV-2. We measured their expression levels in lung tissues of control non- IPF MESHD and IPF MESHD patients, and used murine animal models to study the deterioration of IPF MESHD caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2.Results: In non- IPF MESHD patients, cells expressing ACE2 HGNC and TMPRSS2 HGNC were limited to human alveolar MESHD cells. ACE2 HGNC and TMPRSS2 HGNC were largely upregulated in IPF MESHD patients, and were co-expressed by fibroblast specific protein 1 HGNC ( FSP-1 HGNC)+ lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis MESHD. ACE2 HGNC and TMPRSS2 HGNC were also expressed in FSP-1 HGNC+ lung fibroblasts in bleomycin-inuced pulmonary fibrosis MESHD, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis MESHD and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL‐8, or treatment with reparixin, an inhibitor of IL‐8 receptors CXCR1/2.Conclusions: These data suggest that poor prognosis after COVID-19 MESHD infection caused by air pollution and IPF MESHD is mediated through upregulation of ACE2 and TMPRSS2 in pulmonary fibroblasts, which can be prevented by blocking the IL-8/CXCR1/2 pathway.

    Single-cell RNA-sequencing reveals dysregulation of molecular programs associated with SARS-CoV-2 severity and outcomes in patients with chronic lung disease

    Authors: Linh T. Bui; Nichelle I. Winters; Mei-I Chung; Chitra Joseph; Austin J. Gutierrez; Arun C. Habermann; Taylor S. Adams; Jonas C. Schupp; Sergio Poli; Lance M. Peter; Chase J. Taylor; Jessica B. Blackburn; Bradley W. Richmond; Andrew G. Nicholson; Doris Rassl; William A. Wallace; Ivan O. Rosas; R. Gisli Jenkins; Naftali Kaminski; Jonathan A. Kropski; Nicholas E. Banovich; - Human Cell Atlas Lung Biological Network

    doi:10.1101/2020.10.20.347187 Date: 2020-10-20 Source: bioRxiv

    Rationale: Patients with chronic lung disease MESHD have an increased risk for severe coronavirus disease-19 MESHD ( COVID-19 MESHD) and poor outcomes. Objectives: To identify molecular characteristics of diseased lung epithelial MESHD and immune cells that may account for worse COVID-19 MESHD outcomes in patients with chronic lung diseases MESHD. Methods: We analyzed the transcriptomes of 605,904 single cells isolated from healthy (79 samples) and diseased human lungs (31 chronic obstructive pulmonary disease MESHD ( COPD MESHD), 82 idiopathic pulmonary fibrosis MESHD ( IPF MESHD) and 18 non- IPF MESHD interstitial lung disease MESHD samples). Measurements and Main Results: Cellular distribution and relative expression of SARS-CoV-2 entry factors ( ACE2 HGNC, TMPRSS2 HGNC) was similar in disease and control lungs. Epithelial cells isolated from diseased lungs expressed higher levels of genes linked directly to efficiency of viral replication and the innate immune response. Unique ACE2 HGNC-correlated gene sets were identified for each diagnosis group in the type II alveolar MESHD cells. Diseased lungs MESHD have a significant increase in the proportion of CD4 HGNC, CD8 HGNC and NK cells compared to control lungs. Components of the interferon pathway, the IL6 HGNC cytokine pathway and the major histocompatibility complex (MHC) class II genes are upregulated in several diseased immune cell types. These differences in inflammatory gene expression programs highlight how chronic lung disease MESHD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Conclusions: Chronic lung disease MESHD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence innate and adaptive immune responses to SARS-CoV-2 infection MESHD.

    Expression Pattern of the SARS-CoV-2 Entry Genes ACE2 HGNC and TMPRSS2 HGNC in the Respiratory Tract

    Authors: Yichuan Liu; Hui-Qi Qu; Jingchun Qu; Lifeng Tian; Hakon Hakonarson

    id:10.20944/preprints202005.0040.v2 Date: 2020-09-28 Source: Preprints.org

    To address the expression pattern of the SARS-CoV-2 receptor A CE2 HGNCand the viral priming protease, T MPRSS2, HGNC in the respiratory tract, this study investigated RNA sequencing transcriptome profiling of samples of airway and oral mucosa. As shown, A CE2 HGNChas medium levels of expression in both small airway epithelium and masticatory mucosa, and high levels of expression in nasal epithelium. The expression of A CE2 HGNCis low in mucosal associated invariant T (MAIT) cells, and can’t be detected in alveolar MESHD macrophages. T MPRSS2 HGNCis highly expressed in small airway epithelium and nasal epithelium, and has lower expression in masticatory mucosa. Our results provide the molecular basis that the nasal mucosa is the most susceptible locus in the respiratory tract for SARS-CoV-2 infection MESHD and consequently for subsequent droplet transmission and should be the focus for protection against SARS-CoV-2 infection MESHD.

    Modeling COVID-19 MESHD with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 HGNC Inhibition Against SARS-CoV-2

    Authors: Fuyu Duan; Liyan Guo; Liuliu Yang; Yuling Han; Abhimanyu Thakur; Benjamin E. Nilsson-Payant; Pengfei Wang; Zhao Zhang; Chui Yan Ma; Xiaoya Zhou; Teng Han; Tuo Zhang; Xing Wang; Dong Xu; Xiaohua Duan; Jenny Xiang; Hung-fat Tse; Can Liao; Weiren Luo; Fang-Ping Huang; Ya-Wen Chen; Todd Evans; Robert E. Schwartz; Benjamin tenOever; David D. Ho; Shuibing Chen; Jie Na; Qizhou Lian; Huanhuan Joyce Chen

    doi:10.21203/rs.3.rs-62758/v2 Date: 2020-08-20 Source: ResearchSquare

    Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease MESHD-2019 ( COVID-19 MESHD) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation MESHD. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies.  Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection MESHD. Among the hPSC-derived lung cells, alveolar type II MESHD and ciliated cells are the major cell populations expressing the viral receptor ACE2 HGNC and co-effector TMPRSS2 HGNC, and both were highly permissive to viral infection MESHD. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection MESHD. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 HGNC and IL-18 HGNC, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 HGNC blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper MESHD-inflammatory response mediated by M1 macrophages.    

    Human Embryonic Stem Cell-derived Lung Organoids: a Model for SARS-CoV-2 Infection MESHD and Drug Test

    Authors: Rongjuan Pei; Jianqi Feng; Yecheng Zhang; Hao Sun; Lian Li; Xuejie Yang; Jiangping He; Shuqi Xiao; Jin Xiong; Ying Lin; Kun Wen; Hongwei Zhou; Jiekai Chen; Zhili Rong; Xinwen Chen

    doi:10.1101/2020.08.10.244350 Date: 2020-08-12 Source: bioRxiv

    The coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs MESHD. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer MESHD cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we demonstrated that SARS-CoV-2 infected MESHD and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar MESHD organoids. Ciliated cells, alveolar type 2 MESHD ( AT2 MESHD AT2 HGNC) cells and rare club cells were virus target cells. Electron microscopy captured typical replication, assembly and release ultrastructures and revealed the presence of viruses within lamellar bodies in AT2 HGNC AT2 MESHD cells. Virus infection MESHD induced more severe cell death in alveolar MESHD organoids than in airway organoids. Additionally, RNA-seq revealed early cell response to SARS-CoV-2 infection MESHD and an unexpected downregulation of ACE2 HGNC mRNA. Further, compared to the transmembrane protease, serine 2 ( TMPRSS2 HGNC) inhibitor camostat, the nucleotide analog prodrug Remdesivir potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model for SARS-CoV-2 infection MESHD and drug discovery.

    SARS-CoV-2 Infection MESHD of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

    Authors: Jessie Huang; Adam J Hume; Kristine M Abo; Rhiannon B Werder; Carlos Villacorta-Martin; Konstantinos D Alysandratos; Mary Lou Beermann; Judith Olejnik; Ellen Suder; Esther Bullitt; Anne Hinds; Arjun Sharma; Markus Bosmann; Finn Hawkins; Eric J Burks; Mohsan Saeed; Andrew A Wilson; Elke Mühlberger; Darrell N Kotton

    doi:10.1101/2020.06.30.175695 Date: 2020-06-30 Source: bioRxiv

    ABSTRACTThe most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome MESHD, a clinical phenotype of coronavirus disease 2019 MESHD ( COVID-19 MESHD) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar MESHD epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection MESHD due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present an in vitro human model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial MESHD program. Over time, infected iAT2s exhibit cellular toxicity MESHD that can result in the death of these key alveolar MESHD facultative progenitors, as is observed in vivo in COVID-19 MESHD lung autopsies. Importantly, drug testing using iAT2s confirmed the efficacy of TMPRSS2 HGNC protease inhibition, validating putative mechanisms used for viral entry in human alveolar MESHD cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection, providing a platform for further drug development and facilitating a deeper understanding of COVID-19 MESHD pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 HGNC gene as a potential target for COVID-19 MESHD therapy

    Authors: Aleksei Zarubin; Vadim Stepanov; Anton Markov; Nikita Kolesnikov; Andrey Marusin; Irina Khitrinskaya; Maria Swarovskaya; Sergey Litvinov; Natalia Ekomasova; Murat Dzhaubermezov; Nadezhda Maksimova; Aitalina Sukhomyasova; Olga Shtygasheva; Elza Khusnutdinova; Magomed Radjabov; Vladimir Kharkov

    doi:10.1101/2020.06.20.156224 Date: 2020-06-20 Source: bioRxiv

    The human serine protease TMPRSS2 HGNC gene is involved in the priming of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins being one of the possible targets for COVID-19 MESHD therapy. TMPRSS2 HGNC gene is possibly co-expressed with SARS-CoV-2 cell receptor genes ACE2 HGNC and BSG, but only TMPRSS2 HGNC demonstrates tissue-specific expression in alveolar MESHD cells according to single cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 HGNC gene based on genome-wide data of 76 human populations demonstrates that functionally significant missense mutation in exon 6/7 in TMPRSS2 HGNC gene, was found in many human populations in relatively high frequency, featuring region-specific distribution patterns. The frequency of the missense mutation encoded by the rs12329760, which previously was found to be associated with prostate cancer MESHD, is ranged between 10% and 63% being significantly higher in populations of Asian origin compared to European populations. In addition to SNPs, two copy numbers variants (CNV) were detected in the TMPRSS2 HGNC gene. Number of microRNAs have been predicted to regulate TMPRSS2 HGNC and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well studied drugs can downregulate the expression of TMPRSS2 HGNC in human cells, including Acetaminophen (Paracetamol) and Curcumin. Thus TMPRSS2 HGNC interaction with the SARS-CoV-2, its structural variability, gene-gene interactions, and expression regulation profiles, and pharmacogenomics properties characterize this gene as a potential target for COVID-19 MESHD therapy.

    Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors

    Authors: Kristine M Abo; Liang Ma; Taylor Matte; Jessie Huang; Konstantinos D Alysandratos; Rhiannon B Werder; Aditya Mithal; Mary Lou Beermann; Jonathan Lindstrom-Vautrin; Gustavo Mostoslavsky; Laertis Ikonomou; Darrell N Kotton; Finn Hawkins; Andrew Wilson; Carlos Villacorta-Martin

    doi:10.1101/2020.06.03.132639 Date: 2020-06-04 Source: bioRxiv

    Development of an anti-SARS-CoV-2 therapeutic is hindered by the lack of physiologically relevant model systems that can recapitulate host-viral interactions in human cell types, specifically the epithelium of the lung. Here, we compare induced pluripotent stem cell (iPSC)-derived alveolar MESHD and airway epithelial cells to primary lung epithelial cell controls, focusing on expression levels of genes relevant for COVID-19 MESHD disease modeling. iPSC-derived alveolar epithelial type II MESHD-like cells (iAT2s) and iPSC-derived airway epithelial lineages express key transcripts associated with lung identity in the majority of cells produced in culture. They express ACE2 HGNC and TMPRSS2 HGNC, transcripts encoding essential host factors required for SARS-CoV-2 infection MESHD, in a minor subset of each cell sub-lineage, similar to frequencies observed in primary cells. In order to prepare human culture systems that are amenable to modeling viral infection of both the proximal and distal lung epithelium, we adapt iPSC-derived alveolar MESHD and airway epithelial cells to two-dimensional air-liquid interface cultures. These engineered human lung cell systems represent sharable, physiologically relevant platforms for SARS-CoV-2 infection MESHD modeling and may therefore expedite the development of an effective pharmacologic intervention for COVID-19 MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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