PT  - JOURNAL ARTICLE
AU  - Alan T. Tang
AU  - David W. Buchholz
AU  - Katherine M. Szigety
AU  - Brian Imbhiaka
AU  - Siqi Gao
AU  - Maxwell Frankfurter
AU  - Min Wang
AU  - Jisheng Yang
AU  - Peter Hewins
AU  - Patricia Mericko-Ishizuka
AU  - N Adrian Leu
AU  - Stephanie Sterling
AU  - Isaac A. Monreal
AU  - Julie Sahler
AU  - Avery August
AU  - Xuming Zhu
AU  - Kellie A. Jurado
AU  - Mingang Xu
AU  - Edward E. Morrisey
AU  - Sarah E. Millar
AU  - Hector C. Aguilar
AU  - Mark L. Kahn
TI  - SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice
AID  - 10.1101/2021.12.04.471245
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.04.471245
4099  - http://biorxiv.org/content/early/2021/12/07/2021.12.04.471245.short
4100  - http://biorxiv.org/content/early/2021/12/07/2021.12.04.471245.full
AB  - Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex— events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.Competing Interest StatementThe authors have declared no competing interest.