المؤلفون: Nakayama, Tsuguhisa, Lee, Ivan T, Jiang, Sizun, Matter, Matthias S, Yan, Carol H, Overdevest, Jonathan B, Wu, Chien-Ting, Goltsev, Yury, Shih, Liang-Chun, Liao, Chun-Kang, Zhu, Bokai, Bai, Yunhao, Lidsky, Peter, Xiao, Yinghong, Zarabanda, David, Yang, Angela, Easwaran, Meena, Schürch, Christian M, Chu, Pauline, Chen, Han, Stalder, Anna K, McIlwain, David R, Borchard, Nicole A, Gall, Phillip A, Dholakia, Sachi S, Le, Wei, Xu, Le, Tai, Chih-Jaan, Yeh, Te-Huei, Erickson-Direnzo, Elizabeth, Duran, Jason M, Mertz, Kirsten D, Hwang, Peter H, Haslbauer, Jasmin D, Jackson, Peter K, Menter, Thomas, Andino, Raul, Canoll, Peter D, DeConde, Adam S, Patel, Zara M, Tzankov, Alexandar, Nolan, Garry P, Nayak, Jayakar V

المصدر: Cell Reports Medicine. 2(10)

مصطلحات موضوعية: Dental/Oral and Craniofacial Disease, Tobacco, Prevention, Biodefense, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, Pneumonia, Tobacco Smoke and Health, Clinical Research, Vaccine Related, Lung, 2.1 Biological and endogenous factors, Aetiology, 2.2 Factors relating to the physical environment, Infection, Respiratory, Good Health and Well Being, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, COVID-19, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Nasal Cavity, Respiratory Mucosa, SARS-CoV-2, Serine Endopeptidases, Smokers, Trachea, Viral Tropism, ACE2, IFN-β1, TMPRSS2, ciliated epithelial cell, nasal cavity, smoking, trachea, upper airway

الوصف: Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/09b2v7q5Test

المؤلفون: Li, Xiaoquan, Lidsky, Peter V, Xiao, Yinghong, Wu, Chien-Ting, Garcia-Knight, Miguel, Yang, Junjiao, Nakayama, Tsuguhisa, Nayak, Jayakar V, Jackson, Peter K, Andino, Raul, Shu, Xiaokun

المصدر: PLoS pathogens. 17(9)

مصطلحات موضوعية: Biodefense, Infectious Diseases, Emerging Infectious Diseases, Lung, Prevention, Vaccine Related, Pneumonia, 5.1 Pharmaceuticals, Infection, Microbiology, Immunology, Medical Microbiology, Virology

الوصف: The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3c99k7d7Test

المؤلفون: Lee, Ivan T, Nakayama, Tsuguhisa, Wu, Chien-Ting, Goltsev, Yury, Jiang, Sizun, Gall, Phillip A, Liao, Chun-Kang, Shih, Liang-Chun, Schürch, Christian M, McIlwain, David R, Chu, Pauline, Borchard, Nicole A, Zarabanda, David, Dholakia, Sachi S, Yang, Angela, Kim, Dayoung, Chen, Han, Kanie, Tomoharu, Lin, Chia-Der, Tsai, Ming-Hsui, Phillips, Katie M, Kim, Raymond, Overdevest, Jonathan B, Tyler, Matthew A, Yan, Carol H, Lin, Chih-Feng, Lin, Yi-Tsen, Bau, Da-Tian, Tsay, Gregory J, Patel, Zara M, Tsou, Yung-An, Tzankov, Alexandar, Matter, Matthias S, Tai, Chih-Jaan, Yeh, Te-Huei, Hwang, Peter H, Nolan, Garry P, Nayak, Jayakar V, Jackson, Peter K

المصدر: Nature Communications. 11(1)

مصطلحات موضوعية: Lung, Pneumonia & Influenza, Prevention, Vaccine Related, Infectious Diseases, Biodefense, Clinical Research, Emerging Infectious Diseases, Pneumonia, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Aetiology, Infection, Respiratory, Good Health and Well Being, Age Factors, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme 2, Angiotensin-Converting Enzyme Inhibitors, COVID-19, Cilia, Coronavirus Infections, Endothelial Cells, Gene Expression, Goblet Cells, Humans, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, Respiratory System, Sex Factors, Sinusitis, Smoking

الوصف: The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9152n23bTest