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    Expression of ACE2, TMPRSS2, and CTSL in human airway epithelial cells under physiological and pathological conditions: Implications for SARS-CoV2 infection MESHD

    Authors: Junping Yin; Brigitte Kasper; Frank Petersen; Xinhua Yu

    doi:10.1101/2020.08.06.240796 Date: 2020-08-07 Source: bioRxiv

    SARS-CoV-2 enters into human airway epithelial cells via membrane fusion or endocytosis, and this process is dependent on ACE2, TMPRSS2, and cathepsin L. In this study, we examined the expression profiles of the three SARS-CoV-2 entry-related genes in primary human airway epithelial cells isolated from donors with different physiological and pathological backgrounds such as smoking, COPD, asthma MESHD asthma HP, lung cancer, allergic rhinitis MESHD allergic rhinitis HP, cystic fibrosis MESHD, or viral infections MESHD. By reanalyzing 54 GEO datasets comprising transcriptomic data of 3428 samples, this study revealed that i) smoking is associated with an increased expression of ACE2 and TMPRSS2 and a decreased expression of cathepsin L; ii) infection MESHD of rhinovirus as well as poly(I:C) stimulation leads to high expression of all three SARS-CoV-2 entry-related genes; iii) expression of ACE2 and cathepsin L in nasal epithelial cells are decreased in patients with asthma MESHD asthma HP and allergic rhinitis MESHD allergic rhinitis HP. In conclusion, this study implicates that infection MESHD of respiratory viruses, cigarette smoking and allergic respiratory diseases MESHD might affect the susceptibility to and the development of COVID-19.

    Does Cystic Fibrosis MESHD Constitute an Advantage in COVID-19 Infection MESHD?

    Authors: Valentino Bezzerri; Francesca Lucca; Sonia Volpi; Marco Cipolli

    doi:10.21203/rs.3.rs-53181/v1 Date: 2020-08-04 Source: ResearchSquare

    The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases HP lung diseases MESHD, such as chronic obstructive pulmonary disease MESHD chronic obstructive pulmonary disease HP (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis MESHD (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection MESHD by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.

    Identification of AAV serotypes for lung gene therapy in human embryonic stem cell derived lung organoids.

    Authors: Helena Meyer-Berg; Lucia Zhou Yang; MarĂ­a Pilar de Lucas; Alberto Zambrano; Stephen C. Hyde; Deborah R. Gill

    doi:10.21203/rs.3.rs-40720/v1 Date: 2020-07-08 Source: ResearchSquare

    Gene therapy is being investigated for a range of serious lung diseases MESHD, such as cystic fibrosis MESHD and emphysema MESHD emphysema HP. Recombinant adeno-associated virus (rAAV) is a well-established, safe, viral-vector for gene delivery with multiple natural and artificial serotypes available displaying alternate cell, tissue and species-specific tropisms. Efficient AAV serotypes for the transduction of the conducting airways have been identified for several species; however, efficient serotypes for human lung parenchyma have not yet been identified. Here, we screened the ability of multiple AAV serotypes to transduce lung bud organoids (LBOs) - a model of human lung parenchyma generated from human embryonic stem cells. Microinjection of LBOs allowed us to model transduction from the luminal surface, similar to dosing via vector inhalation. We identified the natural rAAV2 and rAAV6 serotypes, along with synthetic rAAV6 variants, as having tropism for the human lung parenchyma. Positive staining of LBOs for surfactant proteins B and C confirmed distal lung identity and suggested the suitability of these vectors for the transduction of alveolar type II cells. Our findings establish LBOs as a new model for pulmonary gene therapy and stress the relevance of LBOs as a viral infection MESHD model of the lung parenchyma as relevant in SARS-CoV-2 research.

    Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series

    Authors: Andrew G. Weber; Alice S Chau; Mikala Egeblad; Betsy J Barnes; Tobias Janowitz

    doi:10.1101/2020.05.13.20087734 Date: 2020-05-15 Source: medRxiv

    Background Mechanically ventilated patients with coronavirus disease MESHD 2019 (COVID-19) have a mortality of 24-53%, in part due to distal mucopurulent secretions interfering with ventilation. Dornase alfa is recombinant human DNase 1 and digests DNA in mucoid sputum. Nebulized dornase alfa is FDA-approved for cystic fibrosis MESHD treatment. DNA from neutrophil extracellular traps (NETs) contributes to the viscosity of mucopurulent secretions. NETs are found in the serum SERO of patients with severe COVID-19, and targeting NETs reduces mortality in animal models of acute respiratory distress HP syndrome MESHD (ARDS). Thus, dornase alfa may be beneficial to patients with severe COVID-19, acting as a mucolytic and targeting NETs. However, delivery of nebulized drugs can aerosolize SARS-CoV-2, which causes COVID-19, increasing the infection MESHD infection risk TRANS infection risk TRANS risk for staff. Here, we report a single center case series where dornase alfa was administered through an in-line nebulizer system to minimize risk of virus aerosolization. Methods Demographic, clinical data, and outcomes were collected from the electronic medical records of five mechanically ventilated patients with COVID-19, including three requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO), treated with nebulized in-line endotracheal dornase alfa co-administered with albuterol (used to increase delivery to the alveoli), between March 31 and April 24, 2020. Data on tolerability and responses, including longitudinal values capturing respiratory function and inflammatory status, were analyzed. Results Following nebulized in-line administration of dornase alfa with albuterol, the fraction of inspired oxygen requirements was reduced for all five patients. All patients remain alive and two patients have been discharged from the intensive care unit. No drug associated toxicities were identified. Conclusions The results presented in this case series suggest that dornase alfa will be well-tolerated by critically ill patients with COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and two have recently been registered (NCT04359654 and NCT04355364). With this case series, we hope to contribute to the development of management approaches for critically ill patients with COVID-19.

    Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells

    Authors: Vojo Deretic; Graham S Timmins

    doi:10.1101/2020.03.29.008631 Date: 2020-03-31 Source: bioRxiv

    There is interest in the use of chloroquine/hydroxychloroquine (CQ/HCQ) and azithromycin (AZT) in COVID-19 therapy. Employing cystic fibrosis MESHD respiratory epithelial cells, here we show that drugs AZT and ciprofloxacin (CPX) act as acidotropic lipophilic weak bases and confer in vitro effects on intracellular organelles similar to the effects of CQ. These seemingly disparate FDA-approved antimicrobials display a common property of modulating pH of endosomes and trans-Golgi network. We believe this may in part help understand the potentially beneficial effects of CQ/HCQ and AZT in COVID-19, and that the present considerations of HCQ and AZT for clinical trials should be extended to CPX.

The ZB MED preprint Viewer preVIEW includes all COVID-19 related preprints from medRxiv and bioRxiv, from ChemRxiv, from ResearchSquare, from arXiv and from Preprints.org and is updated on a daily basis (7am CET/CEST).

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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