PT  - JOURNAL ARTICLE
AU  - Mariano Carossino
AU  - Paige Montanaro
AU  - Aoife O’Connell
AU  - Devin Kenney
AU  - Hans Gertje
AU  - Kyle A. Grosz
AU  - Susanna A. Kurnick
AU  - Markus Bosmann
AU  - Mohsan Saeed
AU  - Udeni B. R. Balasuriya
AU  - Florian Douam
AU  - Nicholas A. Crossland
TI  - Fatal neuroinvasion of SARS-CoV-2 in K18-hACE2 mice is partially dependent on hACE2 expression
AID  - 10.1101/2021.01.13.425144
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.13.425144
4099  - http://biorxiv.org/content/early/2021/01/15/2021.01.13.425144.short
4100  - http://biorxiv.org/content/early/2021/01/15/2021.01.13.425144.full
AB  - Animal models recapitulating the distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate inflammation in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, SARS-CoV-2 tropism was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis.SUMMARY COVID-19 is a respiratory disease caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease, while lung inflammation remains moderate.Competing Interest StatementThe authors have declared no competing interest.