Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

Smith, John K.; Sausville, Erin L.; Girish, Vishruth; Yuan, Monet Lou; John, Kristen M.; Sheltzer, Jason M.

doi:10.1101/2020.03.28.013672

Cited by 91 publications

(118 citation statements)

References 144 publications

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“…Interestingly, the levels were downregulated to never-smoker levels in former smokers. The results of our analysis are in keeping with several recent reports on ACE2 and smoking (Brake et al, 2020;Leung et al, 2020;Smith and Sheltzer, 2020).…”

Section: Tmprss2 and Ace2 Mrna Expression Increase In Current Smokerssupporting

confidence: 91%

“…This also raises the question of whether other hazards such as high levels of air pollution could have similar effects. Nevertheless, a recent study reports that ACE2 expression is not upregulated by lung disease or exposure to carcinogens (Smith and Sheltzer, 2020). Together, these data suggest that induction of ACE2, and perhaps TMPRSS2, is mediated by specific types of tissue injury.…”

Section: Discussionmentioning

confidence: 86%

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Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2

Baratchian

Berk

et al. 2020

Preprint

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The recent emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed a public health crisis. Higher morbidity and mortality of men with COVID-19 may be explained by androgen-driven mechanisms. One such proposed mechanism is androgen regulation of pulmonary TMPRSS2, the host co-receptor for SARS-CoV-2. We find no evidence for increased TMPRSS2 mRNA expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide does not decrease pulmonary TMPRSS2 expression. Nevertheless, regardless of sex, smoking significantly increases the expression of TMPRSS2, which reverts back to never-smoker levels in former smokers. Finally, we show that in mouse models, despite equivalent AR transcript levels, males express markedly higher amounts of AR protein. If a similar sex-specific regulation of AR protein occurs in human lung, androgens could play important roles in clinical outcome of COVID-19 through mechanisms other than TMPRSS2 regulation.

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Section: Tmprss2 and Ace2 Mrna Expression Increase In Current Smokerssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 86%

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2

Baratchian

Berk

et al. 2020

Preprint

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“…These mouse and human data showed similar trends in expression by bulk RNA-seq, but the sorting strategy employed in this analysis combined epithelial cells of various subtypes. Previous reports have demonstrated expression of Ace2 specifically in AT2 epithelial cells 8,10 ; we sought to determine whether this expression might vary with time. In single cell RNA-seq data for AT2 cells and their embryonic precursors, we found Ace2 and Tmprss2 can be expressed in AT2 cells as early as embryonic day 12 through to P7 ( Figure 3I and S2F).…”

Section: Resultsmentioning

confidence: 99%

“…The importance of ACE2 in maintaining vascular homeostasis suggests that it may also be dynamically regulated in the lung throughout life, which may in turn impact cellular entry and infection by coronaviruses including SARS-CoV-2 20 . Although previous reports have demonstrated expression of ACE2 in various adult cell types within the lung as well as in small intestine, kidney, and testis tissue [8][9][10][11] , we sought to characterize how ACE2 expression changes at the transcript and protein levels across the mammalian lifespan.…”

Section: Resultsmentioning

confidence: 99%

“…In this normal physiological role, ACE2 is expressed on cell membranes in a number of tissues outside the lung. Several single-cell transcriptomic analyses have been performed to determine the tissue and cell type distribution of ACE2 expression [8][9][10][11] . Although they have identified cell types that may be susceptible to infection, these studies generally lack data across different ages and are unable to examine ACE2 translation and localization.…”

Section: Introductionmentioning

confidence: 99%

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Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 disease severity

Inde

Yapp

Joshi

et al. 2020

Preprint

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Angiotensin-converting enzyme 2 (ACE2) maintains cardiovascular and renal homeostasis but also serves as the entry receptor for the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), the causal agent of novel coronavirus disease 2019 (COVID-19). COVID-19 disease severity is typically lower in pediatric patients than adults (particularly the elderly), but higher rates of hospitalizations requiring intensive care are observed in infants than in older children - the reasons for these differences are unknown. ACE2 is expressed in several adult tissues and cells, including alveolar type 2 cells of the distal lung epithelium, but expression at other ages is largely unexplored. Here we show that ACE2 transcripts are expressed in the lung and trachea shortly after birth, downregulated during childhood, and again expressed at high levels in late adulthood. Notably, the repertoire of cells expressing ACE2 protein in the mouse lung and airways shifts during key phases of lung maturation. In particular, podoplanin-positive cells, which are likely alveolar type I cells responsible for gas exchange, express ACE2 only in advanced age. Similar patterns of expression were evident in analysis of human lung tissue from over 100 donors, along with extreme inter- and intra-individual heterogeneity in ACE2 protein expression in epithelial cells. Furthermore, we find that apoptosis, which is a natural host defense system against viral infection, is dynamically regulated during lung maturation, resulting in periods of heightened apoptotic priming and dependence on pro-survival BCL-2 family proteins including MCL-1. Infection of human lung cells with SARS-CoV-2 triggers an unfolded protein stress response and upregulation of the endogenous MCL-1 inhibitor Noxa; in young individuals, MCL-1 inhibition is sufficient to trigger apoptosis in lung epithelial cells and may thus limit virion production and inflammatory signaling. Overall, we identify strong and distinct correlates of COVID-19 disease severity across lifespan and advance our understanding of the regulation of ACE2 and cell death programs in the mammalian lung. Furthermore, our work provides the framework for translation of apoptosis modulating drugs as novel treatments for COVID-19.

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Risk Factors for Severe Outcomes in Patients With Systemic Vasculitis and COVID‐19: A Binational, Registry‐Based Cohort Study

Rutherford

Scott

Karabayas

et al. 2021

Arthritis & Rheumatology

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Objective COVID‐19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and may be at risk of severe outcomes following COVID‐19. We undertook this study to establish the risk factors for severe COVID‐19 outcomes in these patients, including the impact of immunosuppressive therapies. Methods A multicenter cohort was developed through the participation of centers affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes are described. Logistic regression was used to evaluate associations between potential risk factors and a severe COVID‐19 outcome, defined as a requirement for advanced oxygen therapy, a requirement for invasive ventilation, or death. Results The cohort included 65 patients with systemic vasculitis who developed COVID‐19 (median age 70 years, 49% women), of whom 25 patients (38%) experienced a severe outcome. Most patients (55 of 65 [85%]) had antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Almost all patients required hospitalization (59 of 65 [91%]), 7 patients (11%) were admitted to intensive care, and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcomes (adjusted odds ratio [OR] 3.7 [95% confidence interval 1.1–14.9]; P = 0.047), as was comorbid respiratory disease (adjusted OR 7.5 [95% confidence interval 1.9–38.2]; P = 0.006). Vasculitis disease activity and nonglucocorticoid immunosuppressive therapy were not associated with severe outcomes. Conclusion In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID‐19. These data can inform clinical decision‐making relating to the risk of severe COVID‐19 in this vulnerable patient group.

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Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

Cited by 91 publications

References 144 publications

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2

Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 disease severity

Risk Factors for Severe Outcomes in Patients With Systemic Vasculitis and COVID‐19: A Binational, Registry‐Based Cohort Study

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