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; Vasudevan, Anand; John, Kristen M.; Sheltzer, Jason M.

doi:10.1016/j.devcel.2020.05.012

Cited by 361 publications

(421 citation statements)

References 147 publications

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“…Analysis by western blots showed an enhanced level of ACE2 in A549 cells treated by vitamin D2 (Fig. 4), which ts well with data showing the bene t of ACE2 high level as, for example, published Smiths et al These authors documented that tobacco increases the level of ACE2 which prevents the binding of S1 fragment of SARS-CoV-2 to the ACE2 receptor; thus, it prevents the COVID19 progression (Smith et al 2020).…”

Section: Discussionsupporting

confidence: 85%

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Cell differentiation and aging is accompanied by depletion of the ACE2 protein

Bártová

Legartová

Krejčí

et al. 2020

Preprint

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Angiotensin-converting enzyme (ACE) is a zinc metalloproteinase involved in the renin-angiotensin system (RAS). It is well known that ACE and ACE2 are central regulators of blood pressure. Moreover, recently, it was observed that the ACE2 protein is the main target of the SARS-CoV-2 virus, so we have tried to reveal if there is a distinction in the levels of the ACE2 protein in distinct cell types (sensitive to virus infection), during cell differentiation and aging. We observed that depletion of the ACE2 protein appears in aorta-associated parts during the aging of adult mice, and the level of ACE2 was lowest in kidneys of old female animals in comparison to male mice. Differentiation into enterocytes and more pronouncedly into cardiomyocytes was accompanied by depletion of the ACE2 protein. The deficiency of histone deacetylase 1 (HDAC1) also caused a decrease in the level of both ACE2 and its interacting partner renin. However, experimental cardiomyogenesis was associated with renin up-regulation. In human lung adenocarcinoma cells, vitamin D2, but not chloroquine, slightly increased the level of ACE2. Together, the higher level of the ACE2 protein appears in non-differentiated cells and tissue of young mice, in comparisons to terminally differentiated cells and old animals; thus, a higher level of the ACE2 protein, also seen after vitamin D2 treatment, seems to be a barrier against SARS-CoV-2, because it is known that tissues of young individuals are less sensitive to viral infection.

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Section: Discussionsupporting

confidence: 85%

“…But in smokers, it was different. They analyzed gene expression inside the lungs of smokers versus non-smokers, and they saw a considerable spike in ACE2 coming from one particular kind of cell: secretory goblet cells (Smith et al 2020). In our case, we analyzed the heart tissue of young and old male and female animals.…”

Section: Discussionmentioning

confidence: 99%

Cell differentiation and aging is accompanied by depletion of the ACE2 protein

Bártová

Legartová

Krejčí

et al. 2020

Preprint

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“…Previous studies have evaluated ACE2 expression in the respiratory tract. Studies of ACE2 mRNA transcript abundance have provided conflicting interpretations, as well as a lack of protein validation (12)(13)(14)(15)(16)(17)(18)(19). ACE2 protein studies have been limited by a paucity of lung tissue substrates and reports that have yielded contradictory results (20-23) (Supplemental Table 1).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

Bezara

Thurman

Pezzulo

et al. 2020

Preprint

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15Running title: Expression of ACE2 in the human respiratory tract 16 17 Impact: The mapping of ACE2, the receptor for SARS-CoV-2, to specific anatomical regions 18 and to particular cell types in the human respiratory tract will help guide future studies and 19 provide molecular targets for antiviral therapies. We saw no increase of receptor expression in 20 the presence of known risk factors for severe coronavirus disease 2019. 21 22 Abstract: 35 Rationale: Zoonotically transmitted coronaviruses are responsible for three disease 36 outbreaks since 2002, including the current coronavirus disease 2019 pandemic, caused by 37 SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding 38 the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the cellular 39 receptor for SARS-CoV-2. Receptor expression on the cell surface facilitates viral binding and 40 entry. However, reports of the abundance and distribution of ACE2 expression in the respiratory 41 tract are limited and conflicting. Objectives: To determine ACE2 expression in the human 42 respiratory tract and its association with demographic and clinical characteristics. Methods: 43Here, we systematically examined human upper and lower respiratory tract cells using single-cell 44 RNA sequencing and immunohistochemistry to determine where the receptor is expressed. 45Measurements and main results: Our results reveal that ACE2 expression is highest within the 46 sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe 47 disease development, respectively. In the lung parenchyma where severe disease occurs, ACE2 48 was found on the apical surface of a small subset of alveolar type II cells. We saw no increase of 49 receptor expression in the presence of known risk factors for severe coronavirus disease 2019. 50Conclusions: The mapping of ACE2 to specific anatomical regions and to particular cell types in 51 the respiratory tract will help guide future studies and provide molecular targets for antiviral 52 therapies. 53 54 Word count: 223 55

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“…Recently published data suggest, that cells need interferon stimulation to produce ACE2, thereby changing the cell's permissiveness to SARS-CoV-2 and hinting on the dynamic levels of this host factor [19] [20].…”

Section: Selection Of Cell Model Systemsmentioning

confidence: 99%

Screening and testing for a suitable untransfected cell line for SARS-CoV-2 studies

Pommerenke

Rand

Uphoff

et al. 2020

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AbstractAt present, the novel pandemic coronavirus SARS-CoV-2 is a major global threat to human health and hence demands united research activities at different levels. Finding appropriate cell systems for drug screening and testing molecular interactions of the virus with the host cell is mandatory for drug development and understanding the mechanisms of viral entry and replication. For this, we selected human cell lines represented in the Cancer Cell Line Encyclopedia (CCLE) based on RNA-seq data determined transcript levels of ACE2 and TMPRSS2, two membrane proteins that have been identified to aid SARS-CoV-2 entry into the host cell. mRNA and protein expression of these host factors were verified via RQ-PCR and western blot. We then tested permissiveness of these cell lines towards SARS-CoV-2 infection, cytopathic effect, and viral replication finding limited correlation between receptor expression and infectability. One of the candidate cancer cell lines, the human colon cancer cell line CL-14, tested positive for SARS-CoV-2 infection. Our data argue that SARS-CoV-2 in vitro infection models need careful selection and validation since ACE2/TMPRSS2 receptor expression on its own does not guarantee permissiveness to the virus.Author summaryIn the midst of the pandemic outbreak of corona-virus SARS-CoV-2 therapeutics for disease treatment are still to be tested and the virus-host-interactions are to be elucidated. Drug testing and viral studies are commonly conducted with genetically manipulated cells. In order to find a cell model system without genetic modification we screened human cell lines for two proteins known to facilitate entry of SARS-CoV-2. We confirmed and quantified permissiveness of current cell line infection models, but dismissed a number of receptor-positive cell lines that did not support viral replication. Importantly, ACE2/TMPRSS2 co-expression seems to be necessary for viral entry but is not sufficient to predict permissiveness of various cancer cell lines. Moreover, the expression of specific splice variants and the absence of missense mutations of the host factors might hint on successful infection and virus replication of the cell lines.

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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 361 publications

References 147 publications

Cell differentiation and aging is accompanied by depletion of the ACE2 protein

Cell differentiation and aging is accompanied by depletion of the ACE2 protein

Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

Screening and testing for a suitable untransfected cell line for SARS-CoV-2 studies

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