1) We are sharing our manuscript identifying that the SARS-CoV-2 receptor ACE2 is an interferon stimulated gene in human upper airway epithelial cells. Results from an amazing team effort: papers.ssrn.com/sol3/papers.cf… (n/16) 
2) A few weeks ago, as soon as the receptor for SARS-CoV-2 virus (ACE2) and key protease (TMPRSS2) were confirmed, we and @shaleklab started to look through our data sets in collaboration with the @humancellatlas @discovAIR_HCA.
3) In our labs, we use a technique known as single-cell RNA-sequencing (scRNA-seq), which allows us to look at each cell as an individual, rather than an "average" mixture. We focused on ACE2+TMPRSS2+ cells in our datasets taken from human upper airway samples.
4) We found expression in specific subsets of goblet cells that make mucus in the nose. Different viruses tend to go after broader or narrower ranges of cells to enter their host, and this one may have a relatively narrow target.
5) More trainees in the @shaleklab and beyond jumped in, looking through data in upper airway, lungs, and digestive system in human and non-human primate datasets; as these are the sites where initial clinical symptoms have been reported.
6) We found ACE2+TMPRSS2+ at low but reproducible frequencies in the upper airway (goblet), lower lungs (type II pneumocytes), and digestive system (terminal ileum absorptive enterocytes).
7) When we compared differentially expressed genes between ACE2+TMPRSS2+ cells, and their closest neighbors, we all saw patterns of interferon stimulated genes emerge, aligned with others in the HCA arxiv.org/abs/2003.06122.
8) We then asked the question: does interferon directly upregulate ACE2? A quick literature search showed no supporting evidence, and if anything, the opposite trend, at least in cell lines.
9) Regardless, we pushed on experimentally, and by utilizing primary upper airway human epithelial cells we found that IFN-alpha, and to a lesser extent IFN-gamma, induces ACE2 expression in a dose-dependent fashion.
10) We verified these results in public data, and also in an scRNA-seq study of human flu infection.
Why had ACE2 not been included as a canonical ISG before? We noted in our search that we only saw this in primary human epithelial cells, not in immune cells or cell lines.
Why had ACE2 not been included as a canonical ISG before? We noted in our search that we only saw this in primary human epithelial cells, not in immune cells or cell lines.
11) Our discovery that ACE2 is an interferon-stimulated gene (ISG) could have clinical implications, as interferon is often used in the treatment of viral infections as adjunctive therapy, or when no specific antiviral exists.
12) In summary, what we found is that SARS-CoV-2 uses a host receptor that is actually increased by our own body's response to a viral infection. Interferon plays important roles to restrict viruses. Timing, dose and location could be key.
13) Most importantly this study would not have been possible without: @MC_Nawijn, @fabian_theis, @teichlab and @discovAIR_HCA members not on Twitter and support from @shaleklab members: @carlygailz, Sam Allon, Sarah Nyquist, @vincentnmiao and others!
14) And collaborators: @schmidtlabhms, @lingwoodlab, @umass, @ragoninstitute, @broadinstitute, @bostonchildrens, Pittsburgh, @pediatricpulse, @AHRI_News
16) You can dive into the datasets we looked at here: singlecell.broadinstitute.org/single_cell?sc…, with an overview of each here: ordovas-montanes-lab.com/resources
