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Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with neurological sequelae including haemorrhage, thrombosis and ischaemic necrosis and encephalitis. However, the mechanism by which this occurs is unclear. Neurological disease associated with COVID-19 has been proposed to occur following direct infection of the central nervous system and/or indirectly by local or systemic immune activation. We evaluated the expression of angiotensin-converting enzyme-2 and transmembrane protease, serine 2 (TMPRSS2) in brain tissue from five healthy human donors and observed low-level expression of these proteins in cells morphologically consistent with astrocytes, neurons and choroidal ependymal cells within the frontal cortex and medulla oblongata. Primary human astrocytes, neurons, choroid plexus epithelial cells and pericytes supported productive SARS-CoV-2 infection with ancestral, Alpha, Delta and Omicron variants. Infected cells supported the full viral life cycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 can infect human brain cells, and the mechanism of viral entry warrants further investigation.

Keyword(s): brain , COVID-19 , neurological , SARS-CoV-2 and tropism
Funding
This study was supported by the:
  • Ireland Funds (Award 20/COV/8492)
    • Principle Award Recipient: NicolaFletcher
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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/content/journal/jgv/10.1099/jgv.0.002009
2024-07-12
2025-06-15
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References

  1. V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 2021; 19:155–170 [View Article] [PubMed]
    [Google Scholar]
  2. World Health Organization WHO COVID-19 dashboard. n.d https://covid19.who.int accessed 16 August 2023
  3. Jacob F, Pather SR, Huang W-K, Zhang F, Wong SZH et al. Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell 2020; 27:937–950 [View Article] [PubMed]
    [Google Scholar]
  4. Moghimi N, Di Napoli M, Biller J, Siegler JE, Shekhar R et al. The neurological manifestations of post-acute sequelae of SARS-CoV-2 infection. Curr Neurol Neurosci Rep 2021; 21:44 [View Article] [PubMed]
    [Google Scholar]
  5. Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D et al. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell 2020; 27:951–961 [View Article] [PubMed]
    [Google Scholar]
  6. Zhang BZ, Chu H, Han S, Shuai H, Deng J et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res 2020; 30:928–931 [View Article] [PubMed]
    [Google Scholar]
  7. Pedrosa C, Goto-Silva L, Temerozo JR, Souza LRQ, Vitória G et al. Non-permissive SARS-CoV-2 infection in human neurospheres. Stem Cell Res 2021; 54:102436 [View Article] [PubMed]
    [Google Scholar]
  8. Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 2020; 92:699–702 [View Article] [PubMed]
    [Google Scholar]
  9. Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med 2021; 218:e20202135 [View Article] [PubMed]
    [Google Scholar]
  10. Guasp M, Muñoz-Sánchez G, Martínez-Hernández E, Santana D, Carbayo Á et al. CSF biomarkers in COVID-19 associated encephalopathy and encephalitis predict long-term outcome. Front Immunol 2022; 13:866153 [View Article] [PubMed]
    [Google Scholar]
  11. Pilotto A, Odolini S, Masciocchi S, Comelli A, Volonghi I et al. Steroid-responsive encephalitis in coronavirus disease 2019. Ann Neurol 2020; 88:423–427 [View Article] [PubMed]
    [Google Scholar]
  12. Schwabenland M, Salié H, Tanevski J, Killmer S, Lago MS et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 2021; 54:1594–1610 [View Article] [PubMed]
    [Google Scholar]
  13. Mallon PWG, Crispie F, Gonzalez G, Tinago W, Garcia Leon AA et al. Whole-genome sequencing of SARS-Cov-2 in the Republic of Ireland during waves 1 and 2 of the pandemic. MedRxiv 2021 [View Article] [PubMed]
    [Google Scholar]
  14. Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022; 23:3–20 [View Article] [PubMed]
    [Google Scholar]
  15. Matsuyama S, Nao N, Shirato K, Kawase M, Saito S et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S A 2020; 117:7001–7003 [View Article] [PubMed]
    [Google Scholar]
  16. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints12. Am J Epidemiol 1938; 27:493–497 [View Article]
    [Google Scholar]
  17. Purves K, Haverty R, O’Neill T, Folan D, O’Reilly S et al. A novel antiviral formulation containing caprylic acid inhibits SARS-CoV-2 infection of a human bronchial epithelial cell model. J Gen Virol 2023; 104: [View Article] [PubMed]
    [Google Scholar]
  18. Lu X, Wang L, Sakthivel SK, Whitaker B, Murray J et al. US CDC real-time reverse transcription PCR panel for detection of severe acute respiratory syndrome coronavirus 2. Emerg Infect Dis 2020; 26:1654–1665 [View Article] [PubMed]
    [Google Scholar]
  19. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181:271–280 [View Article]
    [Google Scholar]
  20. Wesselingh R. Prevalence, pathogenesis and spectrum of neurological symptoms in COVID-19 and post-COVID-19 syndrome: a narrative review. Med J Aust 2023; 219:230–236 [View Article] [PubMed]
    [Google Scholar]
  21. Keddie S, Pakpoor J, Mousele C, Pipis M, Machado PM et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain 2021; 144:682–693 [View Article] [PubMed]
    [Google Scholar]
  22. Xu E, Xie Y, Al-Aly Z. Long-term neurologic outcomes of COVID-19. Nat Med 2022; 28:2406–2415 [View Article] [PubMed]
    [Google Scholar]
  23. Taquet M, Sillett R, Zhu L, Mendel J, Camplisson I et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry 2022; 9:815–827 [View Article] [PubMed]
    [Google Scholar]
  24. Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL et al. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2007; 292:R373–R381 [View Article] [PubMed]
    [Google Scholar]
  25. Emmi A, Tushevski A, Sinigaglia A, Barbon S, Sandre M et al. ACE2 receptor and TMPRSS2 protein expression patterns in the human brainstem reveal anatomical regions potentially vulnerable to SARS-CoV-2 infection. ACS Chem Neurosci 2023; 14:2089–2097 [View Article] [PubMed]
    [Google Scholar]
  26. Lukiw WJ, Pogue A, Hill JM. SARS-CoV-2 infectivity and neurological targets in the Brain. Cell Mol Neurobiol 2022; 42:217–224 [View Article] [PubMed]
    [Google Scholar]
  27. Kong W, Montano M, Corley MJ, Helmy E, Kobayashi H et al. Neuropilin-1 mediates SARS-Cov-2 infection of astrocytes in brain organoids, inducing inflammation leading to dysfunction and death of neurons. mBio 2022; 13:e0230822 [View Article]
    [Google Scholar]
  28. Andrews MG, Mukhtar T, Eze UC, Simoneau CR, Ross J et al. Tropism of SARS-CoV-2 for human cortical astrocytes. Proc Natl Acad Sci U S A 2022; 119:e2122236119 [View Article] [PubMed]
    [Google Scholar]
  29. Kettunen P, Lesnikova A, Räsänen N, Ojha R, Palmunen L et al. SARS-CoV-2 infection of human neurons Is TMPRSS2 independent, requires endosomal cell entry, and can be blocked by inhibitors of host phosphoinositol-5 kinase. J Virol 2023; 97:e0014423 [View Article] [PubMed]
    [Google Scholar]
  30. Bayati A, Kumar R, Francis V, McPherson PS. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J Biol Chem 2021; 296:100306 [View Article] [PubMed]
    [Google Scholar]
  31. Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 2022; 604:697–707 [View Article] [PubMed]
    [Google Scholar]
  32. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2021; 24:168–175 [View Article] [PubMed]
    [Google Scholar]
  33. Beckman D, Bonillas A, Diniz GB, Ott S, Roh JW et al. SARS-CoV-2 infects neurons and induces neuroinflammation in a non-human primate model of COVID-19. Cell Rep 2022; 41:111573 [View Article] [PubMed]
    [Google Scholar]
  34. Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun 2022; 13:1745 [View Article] [PubMed]
    [Google Scholar]
  35. Torices S, Cabrera R, Stangis M, Naranjo O, Fattakhov N et al. Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection. J Neuroinflammation 2021; 18:167 [View Article] [PubMed]
    [Google Scholar]
  36. Ramani A, Müller L, Ostermann PN, Gabriel E, Abida-Islam P et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J 2020; 39:e106230 [View Article] [PubMed]
    [Google Scholar]
  37. Proust A, Queval CJ, Harvey R, Adams L, Bennett M et al. Differential effects of SARS-CoV-2 variants on central nervous system cells and blood-brain barrier functions. J Neuroinflammation 2023; 20:184 [View Article] [PubMed]
    [Google Scholar]
  38. Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O et al. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci 2022; 45:358–368 [View Article] [PubMed]
    [Google Scholar]
  39. Osborne O, Peyravian N, Nair M, Daunert S, Toborek M. The paradox of HIV blood-brain barrier penetrance and antiretroviral drug delivery deficiencies. Trends Neurosci 2020; 43:695–708 [View Article] [PubMed]
    [Google Scholar]
  40. Lipkin WI, Battenberg EL, Bloom FE, Oldstone MB. Viral infection of neurons can depress neurotransmitter mRNA levels without histologic injury. Brain Res 1988; 451:333–339 [View Article] [PubMed]
    [Google Scholar]
  41. Yang L, Kim TW, Han Y, Nair MS, Harschnitz O et al. SARS-CoV-2 infection causes dopaminergic neuron senescence. Cell Stem Cell 2024; 31:196–211 [View Article] [PubMed]
    [Google Scholar]
  42. Scherbaum R, Kwon EH, Richter D, Bartig D, Gold R et al. Clinical profiles and mortality of COVID-19 inpatients with parkinson’s disease in germany. Mov Disord 2021; 36:1049–1057 [View Article] [PubMed]
    [Google Scholar]
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