{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:44Z","timestamp":1787028464236,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood\u2013brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFR\u03b2 in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood\u2013brain barrier.<\/jats:p>","DOI":"10.3390\/ijms222111622","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"11622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8774-0006","authenticated-orcid":false,"given":"Matteo","family":"Bocci","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, 223 81 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5466-0755","authenticated-orcid":false,"given":"Clara","family":"Oudenaarden","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, 223 81 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"S\u00e0enz-Sard\u00e0","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Division of Pathology, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5081-6604","authenticated-orcid":false,"given":"Joel","family":"Simr\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvid","family":"Ed\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, 413 46 Gothenburg, Sweden"},{"name":"Region V\u00e4stra G\u00f6taland, Department of Infectious Diseases, Sahlgrenska University Hospital, 416 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6992-3415","authenticated-orcid":false,"given":"Jonas","family":"Sj\u00f6lund","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, 223 81 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"M\u00f6ller","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, 223 81 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Gissl\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, 413 46 Gothenburg, Sweden"},{"name":"Region V\u00e4stra G\u00f6taland, Department of Infectious Diseases, Sahlgrenska University Hospital, 416 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Gothenburg, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80 Gothenburg, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK"},{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2708-2443","authenticated-orcid":false,"given":"Elisabet","family":"Englund","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Division of Pathology, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6738-4705","authenticated-orcid":false,"given":"Kristian","family":"Pietras","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University Cancer Centre, Medicon Village, Lund University, 223 81 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study","volume":"395","author":"Chen","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/s41591-020-0968-3","article-title":"Extrapulmonary manifestations of COVID-19","volume":"26","author":"Gupta","year":"2020","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1093\/brain\/awaa240","article-title":"The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings","volume":"143","author":"Paterson","year":"2020","journal-title":"Brain"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1001\/jamaneurol.2020.1127","article-title":"Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China","volume":"77","author":"Mao","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1056\/NEJMc2009787","article-title":"Large-Vessel Stroke as a Presenting Feature of COVID-19 in the Young","volume":"382","author":"Oxley","year":"2020","journal-title":"N Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"R373","DOI":"10.1152\/ajpregu.00292.2006","article-title":"Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system","volume":"292","author":"Doobay","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xu, J., and Lazartigues, E. (2020). Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus. Cell Mol. Neurobiol.","DOI":"10.1007\/s10571-020-00915-1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"C420","DOI":"10.1152\/ajpcell.00409.2004","article-title":"Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes","volume":"290","author":"Gallagher","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/CIRCULATIONAHA.120.052824","article-title":"Lack of Evidence of ACE2 Expression and Replicative Infection by SARSCoV-2 in Human Endothelial Cells","volume":"143","author":"McCracken","year":"2021","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/s41586-018-0590-4","article-title":"Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris","volume":"562","author":"Schaum","year":"2018","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nature25739","article-title":"A molecular atlas of cell types and zonation in the brain vasculature","volume":"554","author":"Vanlandewijck","year":"2018","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"180160","DOI":"10.1038\/sdata.2018.160","article-title":"Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types","volume":"5","author":"He","year":"2018","journal-title":"Sci. Data"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"ref_20","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_21","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_22","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/S0140-6736(20)31305-2","article-title":"Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: A case series","volume":"396","author":"Bradley","year":"2020","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zaigham, M., Holmberg, A., Karlberg, M.L., Lindsjo, O.K., Jokubkiene, L., Sandblom, J., Strand, A.S., Andersson, O., Hansson, S.R., and Nord, D.G. (2021). Intrauterine vertical SARS-CoV-2 infection: A case confirming transplacental transmission followed by divergence of the viral genome. BJOG.","DOI":"10.22541\/au.160616885.53263873\/v1"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, M.-H., Perl, D.P., Nair, G., Li, W., Maric, D., Murray, H., Dodd, S.J., Koretsky, A.P., Watts, J.A., and Cheung, V. (2020). Microvascular Injury in the Brains of Patients with COVID-19. N. Engl. J. Med.","DOI":"10.1056\/NEJMc2033369"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Thakur, K.T., Miller, E.H., Glendinning, M.D., Al-Dalahmah, O., Banu, M.A., Boehme, A.K., Boubour, A.L., Bruce, S.S., Chong, A.M., and Claassen, J. (2021). COVID-19 neuropathology at Columbia University Irving Medical Center\/New York Presbyterian Hospital. Brain.","DOI":"10.1093\/brain\/awab148"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pilotto, A., Masciocchi, S., Volonghi, I., De Giuli, V., Caprioli, F., Mariotto, S., Ferrari, S., Bozzetti, S., Imarisio, A., and Risi, B. (2021). SARS-CoV-2 encephalitis is a cytokine release syndrome: Evidences from cerebrospinal fluid analyses. Clin. Infect. Dis.","DOI":"10.1093\/cid\/ciaa1933"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1754","DOI":"10.1212\/WNL.0000000000010111","article-title":"Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19","volume":"95","author":"Kanberg","year":"2020","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Eden, A., Kanberg, N., Gostner, J., Fuchs, D., Hagberg, L., Andersson, L.M., Lindh, M., Price, R.W., Zetterberg, H., and Gisslen, M. (2020). CSF biomarkers in patients with COVID-19 and neurological symptoms: A case series. Neurology.","DOI":"10.1212\/WNL.0000000000010977"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-021-03710-0","article-title":"Dysregulation of brain and choroid plexus cell types in severe COVID-19","volume":"595","author":"Yang","year":"2021","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C57","DOI":"10.1152\/ajpcell.00426.2020","article-title":"Mitochondrial metabolic manipulation by SARS-CoV-2 in peripheral blood mononuclear cells of patients with COVID-19","volume":"320","author":"Ajaz","year":"2021","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.cell.2020.10.004","article-title":"SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses","volume":"183","author":"Banerjee","year":"2020","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rhea, E.M., Logsdon, A.F., Hansen, K.M., Williams, L.M., Reed, M.J., Baumann, K.K., Holden, S.J., Raber, J., Banks, W.A., and Erickson, M.A. (2020). The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat. Neurosci.","DOI":"10.1038\/s41593-020-00771-8"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature09522","article-title":"Pericytes regulate the blood-brain barrier","volume":"468","author":"Armulik","year":"2010","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/joim.12576","article-title":"Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis","volume":"281","author":"Wahlgren","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nm1787","article-title":"Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke","volume":"14","author":"Su","year":"2008","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature05453","article-title":"Genome-wide atlas of gene expression in the adult mouse brain","volume":"445","author":"Lein","year":"2007","journal-title":"Nature"},{"key":"ref_37","unstructured":"(2020, May 27). Allen Mouse Brain Atlas [Internet]. Seattle (WA): Allen Institute for Brain Science. \u00a92011. Available online: https:\/\/portal.brain-map.org\/atlases-and-data\/rnaseq\/human-multiple-cortical-areas-smart-seq."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13195-019-0534-8","article-title":"CSF evidence of pericyte damage in Alzheimer\u2019s disease is associated with markers of blood-brain barrier dysfunction and disease pathology","volume":"11","author":"Miners","year":"2019","journal-title":"Alzheimers Res. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:32Z","timestamp":1760167292000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,27]]},"references-count":38,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111622"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111622","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.24.445532","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,27]]}}}