المؤلفون: Yang, Junjiao, Xiao, Yinghong, Lidsky, Peter V, Wu, Chien-Ting, Bonser, Luke R, Peng, Shiming, Garcia-Knight, Miguel A, Tassetto, Michel, Chung, Chan-I, Li, Xiaoquan, Nakayama, Tsuguhisa, Lee, Ivan T, Nayak, Jayakar V, Ghias, Khadija, Hargett, Kirsten L, Shoichet, Brian K, Erle, David J, Jackson, Peter K, Andino, Raul, Shu, Xiaokun

المصدر: Nature Microbiology. 8(1)

مصطلحات موضوعية: Emerging Infectious Diseases, Lung, Prevention, Pneumonia & Influenza, Pneumonia, Infectious Diseases, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Aetiology, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Chlorocebus aethiops, Mice, Humans, Animals, SARS-CoV-2, COVID-19, Vero Cells, Angiotensin-Converting Enzyme 2, Peptidyl-Dipeptidase A, Antiviral Agents, Microbiology, Medical Microbiology

الوصف: The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1gz923gnTest

المؤلفون: Saito, Shota, Nakayama, Tsuguhisa, Akutsu, Makoto, Tsunemi, Yasuhiro, Kashiwagi, Takashi, Haruna, Shin-ichi

المصدر: Acta Oto-Laryngologica Case Reports ; volume 9, issue 1, page 53-58 ; ISSN 2377-2484

الإتاحة: https://doi.org/10.1080/23772484.2024.2347351Test

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: Wu, Chien-Ting, Lidsky, Peter V, Xiao, Yinghong, Lee, Ivan T, Cheng, Ran, Nakayama, Tsuguhisa, Jiang, Sizun, Demeter, Janos, Bevacqua, Romina J, Chang, Charles A, Whitener, Robert L, Stalder, Anna K, Zhu, Bokai, Chen, Han, Goltsev, Yury, Tzankov, Alexandar, Nayak, Jayakar V, Nolan, Garry P, Matter, Matthias S, Andino, Raul, Jackson, Peter K

المصدر: Cell Metabolism. 33(8)

مصطلحات موضوعية: Diabetes, Pneumonia & Influenza, Prevention, Lung, Autoimmune Disease, Pneumonia, Infectious Diseases, Emerging Infectious Diseases, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, A549 Cells, Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Antigens, CD, Apoptosis, Apoptosis Regulatory Proteins, COVID-19, Case-Control Studies, Diabetes Mellitus, Female, Host-Pathogen Interactions, Humans, Insulin, Insulin-Secreting Cells, Male, Middle Aged, Neuropilin-1, Receptors, Transferrin, Receptors, Virus, SARS-CoV-2, Serine Endopeptidases, Spike Glycoprotein, Coronavirus, Virus Internalization, ACE2, SARS-CoV-2 spike protein, apoptosis, insulin, neuropilin 1, pancreatic beta cell, phosphoproteomics, type 1 diabetes, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism

الوصف: Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β cells can be infected by SARS-CoV-2 and cause β cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in β cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β cells in patients who succumbed to COVID-19 and selectively infects human islet β cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces β cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β cell killing.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0jt3m3tqTest

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: Goblet Cells, Respiratory System, Lung, Cilia, Endothelial Cells, Humans, Pneumonia, Viral, Coronavirus Infections, Sinusitis, Peptidyl-Dipeptidase A, Angiotensin-Converting Enzyme Inhibitors, Smoking, Age Factors, Sex Factors, Gene Expression, Angiotensin Receptor Antagonists, Pandemics, COVID-19, Angiotensin-Converting Enzyme 2, Pneumonia, Viral

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

المؤلفون: Nakayama, Tsuguhisa, Miyata, Jun, Inoue, Natsuki, Ueki, Shigeharu

المصدر: Allergology International ; volume 72, issue 4, page 521-529 ; ISSN 1323-8930

مصطلحات موضوعية: General Medicine, Immunology and Allergy

الإتاحة: https://doi.org/10.1016/j.alit.2023.06.005Test
https://api.elsevier.com/content/article/PII:S1323893023000692?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1323893023000692?httpAccept=text/plainTest

المؤلفون: Nakashima, Daiki, Nakayama, Tsuguhisa, Minagawa, Syunsuke, Adachi, Tetsuya, Mitsuyama, Chieko, Shida, Yoko, Nakajima, Tsuneya, Haruna, Shin-ichi, Matsuwaki, Yoshinori

المساهمون: Sanofi, Olympus

المصدر: Allergology International ; volume 72, issue 4, page 557-563 ; ISSN 1323-8930

مصطلحات موضوعية: General Medicine, Immunology and Allergy

الإتاحة: https://doi.org/10.1016/j.alit.2023.03.007Test
https://api.elsevier.com/content/article/PII:S1323893023000382?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1323893023000382?httpAccept=text/plainTest

المؤلفون: Wu, Chien-Ting, Lidsky, Peter V., Xiao, Yinghong, Cheng, Ran, Lee, Ivan T., Nakayama, Tsuguhisa, Jiang, Sizun, He, Wei, Demeter, Janos, Knight, Miguel G., Turn, Rachel E., Rojas-Hernandez, Laura S., Ye, Chengjin, Chiem, Kevin, Shon, Judy, Martinez-Sobrido, Luis, Bertozzi, Carolyn R., Nolan, Garry P., Nayak, Jayakar V., Milla, Carlos, Andino, Raul, Jackson, Peter K.

المساهمون: NIH

المصدر: Cell ; volume 186, issue 1, page 112-130.e20 ; ISSN 0092-8674

الإتاحة: https://doi.org/10.1016/j.cell.2022.11.030Test
https://api.elsevier.com/content/article/PII:S0092867422015057?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0092867422015057?httpAccept=text/plainTest

المؤلفون: Inoue, Natsuki, Hirota, Tomomitsu, Hatano, Akihiro, Nakano, Mika, Nakashima, Daiki, Nakayama, Tsuguhisa, Tamari, Mayumi, Yoshikawa, Mamoru

المصدر: Auris Nasus Larynx ; volume 51, issue 2, page 286-294 ; ISSN 0385-8146

مصطلحات موضوعية: General Medicine, Otorhinolaryngology, Surgery

الإتاحة: https://doi.org/10.1016/j.anl.2023.09.007Test
https://api.elsevier.com/content/article/PII:S0385814623001797?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0385814623001797?httpAccept=text/plainTest