{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:30Z","timestamp":1792789650769,"version":"4.5.0"},"reference-count":91,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Biomedical Sciences","award":["RICDIP_2012_Fratta_01"],"award-info":[{"award-number":["RICDIP_2012_Fratta_01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that might lead to very serious consequences. Notably, mental status change, brain confusion, and smell and taste disorders along with neurological complaints have been reported in patients infected with SARS-CoV-2. Furthermore, human brain tissue autopsies from COVID-19 patients show the presence of SARS-CoV-2 neuroinvasion, which correlates with the manifestation of meningitis, encephalitis, leukocyte infiltration, and neuronal damage. The olfactory mucosa has been suggested as a way of entry into the brain. SARS-CoV-2 infection is also known to provoke a hyper-inflammatory reaction with an exponential increase in the production of pro-inflammatory cytokines leading to systemic responses, even in the absence of direct infection of brain cells. Angiotensin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, has been extensively demonstrated to be present in the periphery, neurons, and glial cells in different brain regions. To dissect the details of neurological complications and develop therapies helping COVID-19 survivors regain pre-infection quality of life, the development of robust clinical models is highly warranted. Several human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models have been developed and used for antiviral drug screening and vaccine development, as well as for better understanding of the molecular pathogenetic mechanisms of SARS-CoV-2 infection. In this review, we summarize recent results from the studies involving two such mouse models, namely K18- and CAG-hACE2 transgenics, to evaluate the direct and indirect impact of SARS-CoV-2 infection on the central nervous system.<\/jats:p>","DOI":"10.3390\/molecules27134142","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"4142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["K18- and CAG-hACE2 Transgenic Mouse Models and SARS-CoV-2: Implications for Neurodegeneration Research"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-2179","authenticated-orcid":false,"given":"Simona","family":"Dedoni","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Avdoshina","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4729-9495","authenticated-orcid":false,"given":"Chiara","family":"Camoglio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-3993","authenticated-orcid":false,"given":"Carlotta","family":"Siddi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Fratta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8652-9594","authenticated-orcid":false,"given":"Maria","family":"Scherma","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Fadda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Sardinia, Italy"},{"name":"Institute of Neuroscience-Cagliari, National Research Council, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1002\/mds.28118","article-title":"Can the 2019 Novel Coronavirus Cause Parkinson\u2019s Disease?","volume":"35","author":"Achbani","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Krey, L., Huber, M.K., H\u00f6glinger, G.U., and Wegner, F. (2021). Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson\u2019s Disease?. Brain Sci., 11.","DOI":"10.3390\/brainsci11121654"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dziedzic, A., Saluk-Bijak, J., Miller, E., Niemcewicz, M., and Bijak, M. (2021). The Impact of SARS-CoV-2 Infection on the Development of Neurodegeneration in Multiple Sclerosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041804"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1001\/jamaneurol.2021.0504","article-title":"Overcoming COVID-19 Investigators. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome","volume":"78","author":"LaRovere","year":"2021","journal-title":"JAMA Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMc2019373","article-title":"Neuropathological Features of COVID-19","volume":"383","author":"Solomon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/978-81-322-1777-0_6","article-title":"Neuroinvasive and neurotropic human respiratory coronaviruses: Potential neurovirulent agents in humans","volume":"807","author":"Desforges","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1002\/jmv.25915","article-title":"Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)","volume":"92","author":"Bryce","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S1474-4422(20)30308-2","article-title":"Neuropathology of patients with COVID-19 in Germany: A post-mortem case series","volume":"19","author":"Matschke","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"697329","DOI":"10.3389\/fimmu.2021.697329","article-title":"SARS-CoV-2 Poorly Replicates in Cells of the Human Blood-Brain Barrier Without Associated Deleterious Effects","volume":"12","author":"Constant","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105131","DOI":"10.1016\/j.nbd.2020.105131","article-title":"The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier","volume":"146","author":"Buzhdygan","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40249-020-00662-x","article-title":"Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues","volume":"9","author":"Li","year":"2020","journal-title":"Infect. Dis. Poverty"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1056\/NEJMc2011400","article-title":"Multiorgan and renal tropism of SARS-CoV-2","volume":"383","author":"Puelles","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/alr.22587","article-title":"Smell dysfunction: A biomarker for COVID-19","volume":"10","author":"Moein","year":"2020","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/cid\/ciaa330","article-title":"Self-reported Olfactory and Taste Disorders in Patients with Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study","volume":"71","author":"Giacomelli","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"ofaa199","DOI":"10.1093\/ofid\/ofaa199","article-title":"Olfactory Dysfunction in Coronavirus Disease 2019 Patients: Observational Cohort Study and Systematic Review","volume":"7","author":"Chung","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kumari, P., Rothan, H.A., Natekar, J.P., Stone, S., Pathak, H., Strate, P.G., Arora, K., Brinton, M.A., and Kumar, M. (2021). Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses, 13.","DOI":"10.1101\/2020.12.14.422714"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41593-020-00758-5","article-title":"Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19","volume":"2","author":"Meinhardt","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1016\/j.cell.2021.10.027","article-title":"Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb","volume":"184","author":"Khan","year":"2021","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.stem.2020.10.001","article-title":"SARS-CoV-2 Infects the Brain Choroid Plexus and Disrupts the Blood-CSF Barrier in Human Brain Organoids","volume":"27","author":"Pellegrini","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1001\/jamaneurol.2020.1065","article-title":"The spectrum of neurologic disease in the severe acute respiratory syndrome coronavirus 2 pandemic infection: Neurologists move to the frontlines","volume":"77","author":"Pleasure","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1212\/WNL.0000000000009455","article-title":"Neurologic complications of coronavirus infections","volume":"94","author":"Nath","year":"2020","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1056\/NEJMc2008597","article-title":"Neurologic Features in Severe SARS-CoV-2 Infection","volume":"382","author":"Helms","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"Qin","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_25","first-page":"2178","article-title":"Macrophages: A Trojan horse in COVID-19?","volume":"13","author":"Park","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","first-page":"619","article-title":"Neurological manifestations of COVID-19: Available evidences and a new paradigm","volume":"26","author":"Khatoon","year":"2020","journal-title":"J. Neuro Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"617089","DOI":"10.3389\/fimmu.2020.617089","article-title":"Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins with Tissue Antigens: Implications for Autoimmune Diseases","volume":"11","author":"Vojdani","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/s41577-021-00543-w","article-title":"Autoantibodies in neurological disease","volume":"21","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.cell.2020.09.049","article-title":"A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model","volume":"183","author":"Kreye","year":"2020","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1542\/peds.113.1.e73","article-title":"Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis","volume":"113","author":"Yeh","year":"2004","journal-title":"Pediatrics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1056\/NEJMc2009191","article-title":"Guillain-Barr\u00e9 Syndrome Associated with SARS-CoV-2","volume":"382","author":"Toscano","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1148\/radiol.2020201187","article-title":"COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features","volume":"296","author":"Poyiadji","year":"2020","journal-title":"Radiology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"b158","DOI":"10.1136\/bmj.b158","article-title":"Alzheimer\u2019s disease","volume":"338","author":"Burns","year":"2009","journal-title":"BMJ"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/s41586-022-04569-5","article-title":"SARS-CoV-2 is associated with changes in brain structure in UK Biobank","volume":"604","author":"Douaud","year":"2022","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/00002093-199500091-00006","article-title":"Biologic differences between early- and late-onset Alzheimer disease","volume":"9","author":"Terry","year":"1995","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1007\/s10439-018-02148-2","article-title":"The Shrinking Brain: Cerebral Atrophy Following Traumatic Brain Injury","volume":"47","author":"Harris","year":"2019","journal-title":"Ann. Biomed. Eng."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e106230","DOI":"10.15252\/embj.2020106230","article-title":"SARS-CoV-2 targets neurons of 3D human brain organoids","volume":"39","author":"Ramani","year":"2020","journal-title":"EMBO J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1093\/brain\/awab148","article-title":"COVID-19 neuropathology at Columbia University Irving Medical Center\/New York Presbyterian Hospital","volume":"144","author":"Thakur","year":"2021","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13195-021-00850-3","article-title":"Network medicine links SARS-CoV-2\/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment","volume":"13","author":"Zhou","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S1474-4422(20)30305-7","article-title":"A case of probable Parkinson\u2019s disease after SARS-CoV-2 infection","volume":"19","author":"Cohen","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102377","DOI":"10.1016\/j.msard.2020.102377","article-title":"Multiple sclerosis following SARS-CoV-2 infection","volume":"45","author":"Palao","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8913","DOI":"10.1128\/JVI.74.19.8913-8921.2000","article-title":"Neuroinvasion by human respiratory coronaviruses","volume":"74","author":"Arbour","year":"2000","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wong, T.L., and Weitzer, D.J. (2021). Long COVID and Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS)-A Systemic Review and Comparison of Clinical Presentation and Symptomatology. Medicina, 57.","DOI":"10.3390\/medicina57050418"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s00415-020-09896-z","article-title":"Neurological manifestations associated with COVID-19: A review and a call for action","volume":"267","author":"Leonardi","year":"2020","journal-title":"J. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/978-0-387-33012-9_83","article-title":"Animal models for SARS","volume":"581","author":"Roberts","year":"2006","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.peptides.2005.01.009","article-title":"Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents","volume":"26","author":"Gembardt","year":"2005","journal-title":"Peptides"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"573095","DOI":"10.3389\/fneur.2020.573095","article-title":"The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains","volume":"11","author":"Chen","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_49","first-page":"e0096421","article-title":"The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus","volume":"12","author":"Dong","year":"2021","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1128\/JVI.02012-06","article-title":"Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus","volume":"81","author":"McCray","year":"2007","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cytogfr.2020.05.003","article-title":"The cytokine storm in COVID-19: An overview of the involvement of the chemokine\/chemokine-receptor system","volume":"53","author":"Coperchini","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6122","DOI":"10.1038\/s41467-020-19891-7","article-title":"Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice","volume":"11","author":"Oladunni","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/s41590-020-0779-1","article-title":"The dynamic changes in cytokine responses in COVID-19: A snapshot of the current state of knowledge","volume":"21","author":"Buszko","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1159\/000513040","article-title":"Evidence of SARS-CoV2 Entry Protein ACE2 in the Human Nose and Olfactory Bulb","volume":"209","author":"Klingenstein","year":"2020","journal-title":"Cells Tissues Organs"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e142032","DOI":"10.1172\/jci.insight.142032","article-title":"Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease","volume":"5","author":"Golden","year":"2020","journal-title":"JCI Insight"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.4269\/ajtmh.20-0762","article-title":"Evaluation of K18-hACE2 Mice as a Model of SARS-CoV-2 Infection","volume":"103","author":"Moreau","year":"2020","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1084\/jem.172.4.1127","article-title":"Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain","volume":"172","author":"Perlman","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41392-021-00719-9","article-title":"SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration","volume":"6","author":"Zhang","year":"2021","journal-title":"Sig. Transduct. Target Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11481-020-09975-y","article-title":"SARS-CoV-2 alters blood brain barrier integrity contributing to neuro-inflammation","volume":"16","author":"Reynolds","year":"2021","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41593-020-00771-8","article-title":"The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice","volume":"24","author":"Rhea","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_61","unstructured":"Crunfli, F., Carregari, V.C., and Martins-de-Souza, D. (2021). SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability. medRxiv, preprint."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Rothan, H.A., Kumari, P., Stone, S., Natekar, J.P., Arora, K., Auroni, T.T., and Kumar, M. (2022). SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways. Pathogens, 11.","DOI":"10.3390\/pathogens11020257"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Carossino, M., Kenney, D., O\u2019Connell, A.K., Montanaro, P., Tseng, A.E., Gertje, H.P., Grosz, K.A., Ericsson, M., Huber, B.R., and Kurnick, S.A. (2022). Fatal Neurodissemination and SARS-CoV-2 Tropism in K18-hACE2 Mice Is Only Partially Dependent on hACE2 Expression. Viruses, 14.","DOI":"10.3390\/v14030535"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Ojha","year":"2020","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Shapira, T., Monreal, I.A., Dion, S.P., Jager, M., D\u00e9silets, A., Olmstead, A.D., Vandal, T., Buchholz, D.W., Imbiakha, B., and Gao, G. (2021). A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice. bioRxiv, preprint.","DOI":"10.1101\/2021.05.03.442520"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41586-021-03720-y","article-title":"In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains","volume":"596","author":"Chen","year":"2021","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-020-2943-z","article-title":"COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice","volume":"589","author":"Zheng","year":"2021","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41586-022-04441-6","article-title":"SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters","volume":"603","author":"Halfmann","year":"2022","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-022-04442-5","article-title":"Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron","volume":"603","author":"Shuai","year":"2022","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e14459","DOI":"10.15252\/emmm.202114459","article-title":"Brain cross-protection against SARS-CoV-2 variants by a lentiviral vaccine in new transgenic mice","volume":"13","author":"Ku","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"eabl9929","DOI":"10.1126\/sciimmunol.abl9929","article-title":"Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion","volume":"7","author":"Fumagalli","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1128\/JVI.01702-06","article-title":"Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor","volume":"81","author":"Tseng","year":"2007","journal-title":"J. Virol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1128\/JVI.02272-08","article-title":"Differential virological and immunological outcome of severe acute respiratory syndrome coronavirus infection in susceptible and resistant transgenic mice expressing human angiotensin-converting enzyme 2","volume":"83","author":"Yoshikawa","year":"2009","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e152529","DOI":"10.1172\/jci.insight.152529","article-title":"Highly susceptible SARS-CoV-2 model in CAG promoter-driven hACE2-transgenic mice","volume":"6","author":"Asaka","year":"2021","journal-title":"JCI Insight"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eaav4580","DOI":"10.1126\/sciadv.aav4580","article-title":"A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike","volume":"5","author":"Xia","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41422-020-0305-x","article-title":"Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion","volume":"30","author":"Xia","year":"2020","journal-title":"Cell Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41392-021-00712-2","article-title":"Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation","volume":"6","author":"Xia","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.chom.2020.08.004","article-title":"Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor","volume":"28","author":"Zhao","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1038\/s41467-020-16567-0","article-title":"Vulnerabilities in coronavirus glycan shields despite extensive glycosylation","volume":"11","author":"Watanabe","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"eabm0899","DOI":"10.1126\/scitranslmed.abm0899","article-title":"Vaccination with SARS-CoV-2 spike protein lacking glycan shields elicits enhanced protective responses in animal models","volume":"1","author":"Huang","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1016\/j.cell.2021.03.028","article-title":"N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2","volume":"184","author":"McCallum","year":"2021","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Yu, J., Yao, W., Hu, Y., Wu, S., Li, J., Zhou, H., Hong, K., Chen, J., Liu, L., and Lan, K. (2021). A trimeric NTD and RBD SARS-CoV-2 subunit vaccine induced protective immunity in CAG-hACE2 transgenic mice and rhesus macaques. bioRxiv, 11.","DOI":"10.1101\/2021.11.03.467182"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1073\/pnas.1517719113","article-title":"SARS-like WIV1-CoV poised for human emergence","volume":"113","author":"Menachery","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"741.1","DOI":"10.1096\/fasebj.22.1_supplement.741.1","article-title":"Neuron-targeted expression of ACE2 in the central nervous system prevents angiotensin-II-mediated hypertension","volume":"22","author":"Feng","year":"2008","journal-title":"FASEB J."},{"key":"ref_85","first-page":"450","article-title":"Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection","volume":"57","author":"Yang","year":"2007","journal-title":"Comp. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s11248-021-00249-8","article-title":"Novel transgenic mice with Cre-dependent co-expression of GFP and human ACE2: A safe tool for study of COVID-19 pathogenesis","volume":"30","author":"Bruter","year":"2021","journal-title":"Transgenic Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1126\/science.abb7314","article-title":"Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model","volume":"368","author":"Rockx","year":"2020","journal-title":"Science"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.chom.2020.03.023","article-title":"Infection and rapid transmission of SARS-CoV-2 in ferrets","volume":"27","author":"Kim","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and transmission of SARS-CoV-2 in golden hamsters","volume":"583","author":"Sia","year":"2020","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e0218421","DOI":"10.1128\/jvi.02184-21","article-title":"Evaluating Antibody Mediated Protection against Alpha, Beta, and Delta SARS-CoV-2 Variants of Concern in K18-hACE2 Transgenic Mice","volume":"23","author":"Wong","year":"2022","journal-title":"J. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/s41467-021-21239-8","article-title":"Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody","volume":"11","author":"Rosenfeld","year":"2021","journal-title":"Nat. Commun."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4142\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:35Z","timestamp":1760139575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":91,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27134142"],"URL":"https:\/\/doi.org\/10.3390\/molecules27134142","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}