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New research from @joans and me on COVID-19: smoking triggers the expansion of a subpopulation of lung cells that express the coronavirus receptor ACE2. https://www.biorxiv.org/content/10.1101/2020.03.28.013672v1 …pic.twitter.com/uPlQaJKFbI
In general, three factors have been linked with COVID-19 susceptibility: being male, being elderly, and smoking. For instance, in one cohort, 12.3% of current smokers required ventilators, were admitted to an ICU, or died, compared to <5% of non-smokers.https://www.nejm.org/doi/full/10.1056/NEJMoa2002032 …
We were interested in uncovering whether any of these factors affected the expression of ACE2, the receptor that SARS-CoV-2 uses to enter human cells, in the respiratory tract.
We collected gene expression data from published experiments in mice, rats, and humans and looked to see whether age and sex had an effect on ACE2. In general, we didn’t see significant differences in lung ACE2 between young/old or female/male mice, rats, and humans.pic.twitter.com/ln7iSMrxNP
But, when we looked at smoking, we saw a consistent, dose-dependent up-regulation of ACE2 in the lungs of human smokers and mice exposed to smoke.pic.twitter.com/bd8ENy1dGZ
This up-regulation was specific for smoke exposure. If we looked at data from other lung diseases, like asthma and cystic fibrosis, or other carcinogens, like arsenic or radiation, we didn’t see any changes in ACE2 levels.pic.twitter.com/r2zfG1iAC8
So what causes this upregulation? To try to figure that out, we looked at single-cell RNA-Seq data to see which cells in the respiratory tract express ACE2.
We saw ACE2 in alveolar type 2 cells, which several others have reported, but we also saw it in lung secretory cells (goblet and club cells) that express mucins like MUC5AC and MUC5B.pic.twitter.com/XsMfuH6YSz
This suggested an explanation for the increase in ACE2 in smokers’ lungs. Chronic exposure to cigarette smoke is known to triggers the expansion of secretory goblet cells, which produce mucus to protect the respiratory epithelium from inhaled irritants. https://www.atsjournals.org/doi/full/10.1164/ajrccm.161.3.9907080 …
So, we hypothesized: there are epithelial stem cells (KRT5+) that are ACE2-. Smoke causes them to differentiate and expand into MUC5AC+ ACE2+ goblet cells. Looking at single-cell data from non-smokers and smokers, we can see this happening:pic.twitter.com/9HZPwQ8M3Z
And, these observations can be recapitulated experimentally. If you differentiate lung cells in vitro, ACE2 is upregulated – and if you differentiate lung cells in the presence of smoke, you see more ACE2 than with air alone.pic.twitter.com/5t0DmBO9hA
So, we think that ACE2 is expressed in a sub-population of mucus-secreting cells that expand in response to smoke exposure. This could explain the increase in ACE2 in smokers’ lungs.
One outstanding question: how much does ACE2 expression matter for COVID-19 susceptibility? We don’t really know – smokers may have lots of co-morbidities that make them vulnerable to COVID-19. But –
Among transgenic mice engineered to express human ACE2, higher hACE2 caused shorter survival when challenged with the 2003 SARS coronavirus. So, that’s some evidence that it could have a direct effect coronavirus infections. https://www.ncbi.nlm.nih.gov/pubmed/17079315 pic.twitter.com/BBbI2OiTlb
And, this is something that people have control over! We show that quitting smoking is associated with a decrease in lung ACE2 expression. I’m not an MD, but when faced with an epidemic respiratory virus, giving up cigarettes is probably a good idea - for multiple reasons.pic.twitter.com/hekOpnYAkt
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