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Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.<\/jats:p>","DOI":"10.3390\/v14051020","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T23:08:36Z","timestamp":1652396916000},"page":"1020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse"],"prefix":"10.3390","volume":"14","author":[{"given":"Frauke","family":"Seehusen","sequence":"first","affiliation":[{"name":"Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-7883","authenticated-orcid":false,"given":"Jordan 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Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishanthi","family":"Subramaniam","sequence":"additional","affiliation":[{"name":"Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Wunderlin-Giuliani","sequence":"additional","affiliation":[{"name":"Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7567-7185","authenticated-orcid":false,"given":"Grant L.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected Tropical Disease, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-0848","authenticated-orcid":false,"given":"Edward I.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected Tropical Disease, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-8926","authenticated-orcid":false,"given":"Benedict D.","family":"Michael","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology and NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Department of Neurology, The Walton Centre NHS Foundation 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