Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response

Purkayastha, Arunima; Sen, Chandani; García, Gustavo; Langerman, Justin; Vijayaraj, Preethi; Shia, David W.; Meneses, Luisa K.; Rickabaugh, Tammy M.; Mulay, Apoorva; Konda, Bindu; Sim, Myung Shin; Stripp, Barry R.; Plath, Kathrin; Arumugaswami, Vaithilingaraja; Gomperts, Brigitte N.

doi:10.1101/2020.07.28.226092

Cited by 20 publications

(33 citation statements)

References 26 publications

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“…Thus, the observed synergy can be due to the effects on independent targets. Lastly, we tested berzosertib in a primary human lung tissue culture system consisting of mucociliary air-liquid interface (ALI) cultures derived from primary human tissue (Purkayastha et al, 2020). In this ALI system, as well, berzosertib was effective in inhibiting SARS-CoV-2 (Figures 4A and 4B).…”

Section: Resultsmentioning

confidence: 99%

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

et al. 2021

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SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug screening system and identified a small molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-Damage Response that are critical for SARS-CoV-2 infection. A drug-protein interaction based secondary screen confirmed compounds such as the ATR kinase inhibitor berzosertib and torin2 with anti SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and MERS-CoV as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.

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Section: Resultsmentioning

confidence: 99%

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

et al. 2021

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“…Smoking-mediated upregulation of the androgen pathway also leads to an increased SARS-CoV-2 susceptibility [26]. Acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke [27]. The radiological manifestation of COVID-19 is mainly peripheral ground-glass opacity while age, smoking and hypertension were used to predict the severity of COVID-19 disease [28].…”

Section: Resultsmentioning

confidence: 99%

Tobacco use as a well-recognized cause of severe COVID-19 manifestations

Gupta

Nethan

Mehrotra

2021

Respiratory Medicine

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Introduction: The Coronavirus disease (COVID-19) infection is caused by the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) primarily affecting the lungs. All tobacco-related illnesses including asthma, chronic obstructive pulmonary disease (COPD), and coronary artery disease are known to reduce the lung capacity and impair the immune system of the body and can greatly influence the ability to fight the novel coronavirus. The purpose of this state-of-the-art literature review is to summarize the evidence of the association of tobacco use with the severity of the COVID-19 manifestations. Method: Articles describing the association of tobacco use with the severity of COVID-19 manifestations were searched on PubMed, MEDLINE, and Google. This review covers the relevant studies on the subject published from January 1, 2020 to September 10, 2020. Results: Tobacco use in all forms, whether smoking or chewing, is significantly associated with severe COVID-19 outcomes. Pre-existing comorbidities in tobacco users such as cardiovascular diseases, diabetes, respiratory diseases and hypertension were found to further aggravate the disease manifestations making the treatment of such COVID-19 patients more challenging due to their rapid clinical deterioration. Conclusions: Current review indicates that nicotine exposure is linked to cardiopulmonary vulnerability to COVID-19 and tobacco use can be a potential risk factor for not only getting the viral infection but also its severe manifestations. The current pandemic provides a teachable moment to break the cycle of nicotine addiction and accelerate national tobacco control programs to achieve a tobacco-free world.

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“…44 Purkayastha and colleagues, through modeling the direct effects of cigarette smoke on SARS-CoV-2 infection, showed that acute cigarette smoke exposure increases the number of infected and apoptotic cells, prevents the normal airway basal stem cell repair response, suggesting that smoke increases COVID-19 severity. 46 However, it has been shown that smoking was not associated with increased mortality in COVID-19 pneumonia 47,48 , but cumulative smoking exposure, as measured by pack/years, was associated with a higher risk of hospitalization and mortality from COVID-19 in a dose-dependent manner. 49 In contrast, cigarette smokepretreatment potently abrogates SARS-CoV-2 replication in an vitro model 41 .…”

Section: Discussionmentioning

confidence: 98%

Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

Silva

Falcoff

Corradi

et al. 2021

Preprint

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Rationale—Angiotensin converting enzyme (ACE) 2 and the transmembrane protease serine 2 (TMPRSS2) are key for cellular entry of the type 2 coronavirus that causes severe acute respiratory syndrome (SARS-CoV2), the etiological agent of coronavirus-19 disease (COVID-19). There has been a growing concern that renin-angiotensin system (RAS) blockade with ACE inhibitors (ACEIs) or type 1 angiotensin (Ang II) receptor blockers (ARBs) increases ACE2 expression and then elevate patient susceptibility to SARS-CoV-2. However, evidence about RAS blockade and ACE2 in human lung are lacking.Objective– To investigate RAS blockade on ACE2 and TMPRSS2 in type II pneumocytes of human lung parenchymal of untreated and ACEI/ARB-treated hypertensive subjects.Methods and Results– ACE2 and TMPRSS2 protein expression were measured by immunohistochemistry. We found that smoking and RAS blockade influence on the percentage of human ACE2-expressing type II pneumocytes (p= 0.026). Smokers subjects under RAS blockade treatment exhibited higher percentage of ACE2-expressing type II pneumocytes than normotensive ones. Within the ACEI/ARB-treated group, the percentage of ACE2-expressing type II pneumocytes was higher in smokers than never smokers. A significant association between ACE2 immunostaining intensity and smoking on subjects over 60 years old was found (p= 0.05): older smokers exhibited higher ACE2 protein levels compared to youngers. The percentage of TMPRSS2-expressing type II pneumocytes was greater in men than women (p= 0.026) and in subjects under 60 years old (p= 0.040) and trend to be higher in ACEI/ARB-treated subjects than normotensives (p= 0.060). A significant association between TMPRSS2 immunostaining intensity with smoking and age or with RAS blockade and age or with RAS blockade and smoking was observed. Older or smokers subjects under ACEI/ARB treatment exhibited higher TMPRSS2 protein levels than youngers or never smokers.Conclusions—ACE2 and TMPRSS2 are influenced by smoking and ACEI/ARB treatment. These findings help explain the increased susceptibility to COVID-19 in subjects with treated cardiovascular-related pathologies.

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Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response

Cited by 20 publications

References 26 publications

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication

Tobacco use as a well-recognized cause of severe COVID-19 manifestations

Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

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