Angiotensin Converting Enzyme II (ACE2), an entry receptor for SARS-COV-2, is expressed in respiratory epithelia as two isoforms; a canonical isoform (long ACE2) and a shorter isoform (short ACE2), the latter of which is regulated by IFNs and antiviral cytokines. Bulk RNAseq data (n=26) from healthy controls, patients with allergic rhinitis and COPD, demonstrated variability in expression of these isoform ratios, with short ACE2 more highly expressed in the nasal (PNEC) than bronchial airway cells (PBEC). RNAfish experiments showed that short ACE2 is primarily expressed in submucosal glands and airway multiciliated epithelial cells. CRISPR-Cas9 KO of the ACE2 isoforms in PNEC revealed that those lacking short ACE-2 were able to support SARS-CoV-2 infection whereas those lacking long ACE2 were not (Fig1). ACE2 isoform overexpression studies and Bio-ID in PBEC are currently underway to assess if high levels of short ACE2 expression might have a protective role. Should this be the case, changes in the inflammatory cytokine profile resulting from overexpressing short ACE2 cells, both in the presence and absence of SARS-CoV-2 infection, may allow cytokine signatures to be identified that either predict and/or provide mechanistic insight into the causes of severe SARS-CoV-2 respiratory disease.