Running Title: Spatiotemporal analysis of SARS-CoV-2 and hACE2 in K18-hACE2

37 Animal models recapitulating the distinctive features of severe COVID-19 are critical to 38 enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing 39 human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter 40 (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) 41 and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated 42 the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. 43 Despite infection and moderate inflammation in the lungs, lethality was invariably 44 associated with viral neuroinvasion and neuronal damage (including spinal motor 45 neurons). Neuroinvasion occurred following virus transport through the olfactory 46 neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, 47 SARS-CoV-2 tropism was overall neither widespread among nor restricted to only 48 ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 49 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model 50 as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis. 51