Abstract
Animal models recapitulating COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Intranasally inoculated transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. We evaluated the clinical and virological dynamics of SARS-CoV-2 using two intranasal doses (10 4 and 10 6 PFUs), with a detailed spatiotemporal pathologic analysis of the 10 6 dose cohort. Despite generally mild-to-moderate pneumonia, clinical decline resulting in euthanasia or death was commonly associated with hypothermia and viral neurodissemination independent of inoculation dose. Neuroinvasion was first observed at 4 days post-infection, initially restricted to the olfactory bulb suggesting axonal transport via the olfactory neuroepithelium as the earliest portal of entry. Absence of viremia suggests neuroinvasion occurs independently of transport across the blood-brain barrier. SARS-CoV-2 tropism was neither restricted to ACE2-expressing cells (e.g., AT1 pneumocytes), nor inclusive of some ACE2-positive cell lineages (e.g., bronchiolar epithelium and brain vasculature). Absence of detectable ACE2 protein expression in neurons but overexpression in neuroepithelium suggest this as the most likely portal of neuroinvasion, with subsequent ACE2 independent lethal neurodissemination. A paucity of epidemiological data and contradicting evidence for neuroinvasion and neurodissemination in humans call into question the translational relevance of this model.
Keywords: comparative pathology; immunohistochemistry; in situ hybridization; in vivo imaging; translational animal model; transmission electron microscopy; viral pathogenesis.
【저자키워드】 immunohistochemistry, in vivo imaging, transmission electron microscopy, In situ hybridization, Viral pathogenesis., comparative pathology, translational animal model, 【초록키워드】 COVID-19, SARS-CoV-2, immunohistochemistry, ACE2, Pneumonia, SARS-COV-2 infection, Human, viral pathogenesis, Transmission, animal models, Brain, hACE2, Cohort, Viremia, olfactory bulb, animal, Lineage, death, blood-brain barrier, epidemiological data, vasculature, in vivo, transmission electron microscopy, expression, Critical, SARS-CoV-2 pathogenesis, intranasal, In situ hybridization, K18-hACE2, Human angiotensin-converting enzyme 2, neurons, Evidence, Pneumocytes, AT1, Analysis, dose, angiotensin, ACE2 protein, Mild-to-moderate, olfactory, Neuron, independent of, portal, Transport, hypothermia, Virological, human Angiotensin-converting enzyme, transgenic mice, cytokeratin 18 promoter, cytokeratin, overexpression, ACE2-expressing cells, PFUs, euthanasia, spatiotemporal, Cell, axonal transport, independent, olfactory neuroepithelium, ENhance, neuroepithelium, resulting, inoculated, pathologic, bronchiolar, subsequent, detectable, evaluated, question, occur, expressing, days post-infection, translational, ACE2-expressing cell, 【제목키워드】 SARS-CoV-2, tropism, Dependent,