Non-permissive SARS-CoV-2 Infection in Human Neurospheres

Coronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that several other organs are affected, including the brain. Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but the neurotropic potential of the virus is still debated. Herein, we sought to investigate SARS-CoV-2 infection in human neural cells. We demonstrated that SARS-CoV-2 infection of neural tissue is non-permissive, however, it can elicit inflammatory response and cell damage. These findings add to the hypothesis that most of the neural damage caused by SARS-CoV-2 infection is due to a systemic inflammation leading to indirect harmful effects on the central nervous system despite the absence of local viral replication.

Citing Articles

iPSC-derived human cortical organoids display profound alterations of cellular homeostasis following SARS-CoV-2 infection and Spike protein exposure.

Cappelletti G, Brambilla L, Strizzi S, Limanaqi F, Melzi V, Rizzuti M FASEB J. 2025; 39(4):e70396.

PMID: 39950320 PMC: 11826378. DOI: 10.1096/fj.202401604RRR.

SARS-CoV-2 Infection of the Central Nervous System: A Case Report.

Valkov T, Argirova R, Dimitrov G Viruses. 2025; 16(12.

PMID: 39772268 PMC: 11728493. DOI: 10.3390/v16121962.

Neuropsychiatric Burden of SARS-CoV-2: A Review of Its Physiopathology, Underlying Mechanisms, and Management Strategies.

Pacnejer A, Butuca A, Dobrea C, Arseniu A, Frum A, Gligor F Viruses. 2025; 16(12.

PMID: 39772122 PMC: 11680421. DOI: 10.3390/v16121811.

Characterizing neuroinvasion and neuropathology of SARS-CoV-2 by using AC70 human ACE2 transgenic mice.

Hsu J, Saenkham-Huntsinger P, Huang P, Octaviani C, Drelich A, Peng B Front Microbiol. 2024; 15:1455462.

PMID: 39380676 PMC: 11458418. DOI: 10.3389/fmicb.2024.1455462.

Saxitoxin potentiates human neuronal cell death induced by Zika virus while sparing neural progenitors and astrocytes.

Souza L, Pedrosa C, Puig-Pijuan T, da Silva Dos Santos C, Vitoria G, Delou J Sci Rep. 2024; 14(1):22809.

PMID: 39354036 PMC: 11445263. DOI: 10.1038/s41598-024-73873-z.

References

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

De Felice F, Tovar-Moll F, Moll J, Munoz D, Ferreira S . Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System. Trends Neurosci. 2020; 43(6):355-357. PMC: 7172664. DOI: 10.1016/j.tins.2020.04.004. View

Laamarti M, Alouane T, Kartti S, Chemao-Elfihri M, Hakmi M, Essabbar A . Large scale genomic analysis of 3067 SARS-CoV-2 genomes reveals a clonal geo-distribution and a rich genetic variations of hotspots mutations. PLoS One. 2020; 15(11):e0240345. PMC: 7654798. DOI: 10.1371/journal.pone.0240345. View

Hadfield J, Megill C, Bell S, Huddleston J, Potter B, Callender C . Nextstrain: real-time tracking of pathogen evolution. Bioinformatics. 2018; 34(23):4121-4123. PMC: 6247931. DOI: 10.1093/bioinformatics/bty407. View

Lopez-Diaz A, Ayesa-Arriola R, Crespo-Facorro B, Ruiz-Veguilla M . COVID-19 Infection During Pregnancy and Risk of Neurodevelopmental Disorders in Offspring: Time for Collaborative Research. Biol Psychiatry. 2020; 89(5):e29-e30. PMC: 7604160. DOI: 10.1016/j.biopsych.2020.09.011. View

McCoy M, Tansey M . TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008; 5:45. PMC: 2577641. DOI: 10.1186/1742-2094-5-45. View

Liu M, Wang T, Zhou Y, Zhao Y, Zhang Y, Li J . Potential Role of ACE2 in Coronavirus Disease 2019 (COVID-19) Prevention and Management. J Transl Int Med. 2020; 8(1):9-19. PMC: 7227161. DOI: 10.2478/jtim-2020-0003. View

Kumar S, Stecher G, Li M, Knyaz C, Tamura K . MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. Mol Biol Evol. 2018; 35(6):1547-1549. PMC: 5967553. DOI: 10.1093/molbev/msy096. View

Bradley B, Maioli H, Johnston R, Chaudhry I, Fink S, Xu H . Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet. 2020; 396(10247):320-332. PMC: 7365650. DOI: 10.1016/S0140-6736(20)31305-2. View

10.

Phan T . Genetic diversity and evolution of SARS-CoV-2. Infect Genet Evol. 2020; 81:104260. PMC: 7106203. DOI: 10.1016/j.meegid.2020.104260. View

11.

Garcez P, Loiola E, Madeiro da Costa R, Higa L, Trindade P, Delvecchio R . Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016; 352(6287):816-8. DOI: 10.1126/science.aaf6116. View

12.

Corman V, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu D . Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020; 25(3). PMC: 6988269. DOI: 10.2807/1560-7917.ES.2020.25.3.2000045. View

13.

Woodruff G, Phillips N, Carromeu C, Guicherit O, White A, Johnson M . Screening for modulators of neural network activity in 3D human iPSC-derived cortical spheroids. PLoS One. 2020; 15(10):e0240991. PMC: 7581002. DOI: 10.1371/journal.pone.0240991. View

14.

Dobrindt K, Hoagland D, Seah C, Kassim B, OShea C, Murphy A . Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection. Stem Cell Reports. 2021; 16(3):505-518. PMC: 7881728. DOI: 10.1016/j.stemcr.2021.02.010. View

15.

Koyama T, Platt D, Parida L . Variant analysis of SARS-CoV-2 genomes. Bull World Health Organ. 2020; 98(7):495-504. PMC: 7375210. DOI: 10.2471/BLT.20.253591. View

16.

Mallapaty S . Mini organs reveal how the coronavirus ravages the body. Nature. 2020; 583(7814):15-16. DOI: 10.1038/d41586-020-01864-x. View

17.

Fifi J, Mocco J . COVID-19 related stroke in young individuals. Lancet Neurol. 2020; 19(9):713-715. PMC: 7434432. DOI: 10.1016/S1474-4422(20)30272-6. View

18.

Cornillez-Ty C, Liao L, Yates 3rd J, Kuhn P, Buchmeier M . Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J Virol. 2009; 83(19):10314-8. PMC: 2748024. DOI: 10.1128/JVI.00842-09. View

19.

Pinto B, Oliveira A, Singh Y, Jimenez L, Goncalves A, Ogava R . ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19. J Infect Dis. 2020; 222(4):556-563. PMC: 7377288. DOI: 10.1093/infdis/jiaa332. View

20.

Barrantes F . The unfolding palette of COVID-19 multisystemic syndrome and its neurological manifestations. Brain Behav Immun Health. 2021; 14:100251. PMC: 8019247. DOI: 10.1016/j.bbih.2021.100251. View