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Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers.

ABSTRACT: 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.

SUBMITTER: Nakayama T

PROVIDER: S-EPMC8479532 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers.

Nakayama Tsuguhisa T Lee Ivan T IT Jiang Sizun S Matter Matthias S MS Yan Carol H CH Overdevest Jonathan B JB Wu Chien-Ting CT Goltsev Yury Y Shih Liang-Chun LC Liao Chun-Kang CK Zhu Bokai B Bai Yunhao Y Lidsky Peter P Xiao Yinghong Y Zarabanda David D Yang Angela A Easwaran Meena M Schürch Christian M CM Chu Pauline P Chen Han H Stalder Anna K AK McIlwain David R DR Borchard Nicole A NA Gall Phillip A PA Dholakia Sachi S SS Le Wei W Xu Le L Tai Chih-Jaan CJ Yeh Te-Huei TH Erickson-Direnzo Elizabeth E Duran Jason M JM Mertz Kirsten D KD Hwang Peter H PH Haslbauer Jasmin D JD Jackson Peter K PK Menter Thomas T Andino Raul R Canoll Peter D PD DeConde Adam S AS Patel Zara M ZM Tzankov Alexandar A Nolan Garry P GP Nayak Jayakar V JV

Cell reports. Medicine 20210928 10

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 ...[more]

PMID: 34604819

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019, and the resulting pandemic has already caused the death of over 6 million people. There are currently few antivirals approved for treatment of the 2019 coronavirus disease (COVID-19), and more options would be beneficial, not only now but also to increase our preparedness for future coronavirus outbreaks. Honokiol is a small molecule from magnolia trees for which several biological effects have been reported, including anticancer and anti-inflammatory activities. Honokiol has also been shown to inhibit several viruses in cell culture. In this study, we determined that honokiol protected Vero E6 cells from SARS-CoV-2-mediated cytopathic effect, with a 50% effective concentration of 7.8 μM. In viral load reduction assays, honokiol decreased viral RNA copies as well as viral infectious progeny titers. The compound also inhibited SARS-CoV-2 replication in the more relevant human A549 cells expressing angiotensin converting enzyme 2 and transmembrane protease serine 2. Time-of-addition and other assays showed that honokiol inhibited virus replication at a post-entry step of the replication cycle. Honokiol was also effective against more recent variants of SARS-CoV-2, including Omicron, and it inhibited other human coronaviruses as well. Our study suggests that honokiol is an interesting molecule to be evaluated further in animal studies and, when successful, maybe even in clinical trials to investigate its effect on virus replication and pathogenic (inflammatory) host responses. IMPORTANCE Honokiol is a compound that shows both anti-inflammatory and antiviral effects, and therefore its effect on SARS-CoV-2 infection was assessed. This small molecule inhibited SARS-CoV-2 replication in various cell-based infection systems, with up to an ~1,000-fold reduction in virus titer. In contrast to earlier reports, our study clearly showed that honokiol acts on a postentry step of the replication cycle. Honokiol also inhibited different recent SARS-CoV-2 variants and other human coronaviruses (Middle East respiratory syndrome CoV and SARS-CoV), demonstrating its broad spectrum of antiviral activity. The anticoronavirus effect, combined with its anti-inflammatory properties, make honokiol an interesting compound to be further explored in animal coronavirus infection models.

Dataset Information

Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers.

Publications

Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers.

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