Neuropathogenesis of SARS-CoV-2 in human neuronal, microglial and glial cells.
COVID-19
Genomics
Neuropathogenesis
Neurotropism
SARS-CoV-2
Ultrastructure
Journal
Archives of microbiology
ISSN: 1432-072X
Titre abrégé: Arch Microbiol
Pays: Germany
ID NLM: 0410427
Informations de publication
Date de publication:
08 Jul 2024
08 Jul 2024
Historique:
received:
12
04
2024
accepted:
28
06
2024
medline:
8
7
2024
pubmed:
8
7
2024
entrez:
8
7
2024
Statut:
epublish
Résumé
Neurological complications, both acute and chronic, are reported commonly in COVID-19 affected individuals. In this context, the understanding of pathogenesis of SARS-CoV-2 in specific cells of central nervous system (CNS) origin is relevant. The present study explores infection biology of a clinical isolate of SARS-CoV-2 in human cell lines of neural origin such as the glioblastoma (U87-MG), neuroblastoma (SHSY5Y) and microglia (C20). Despite showing clear evidence of infection by immunofluorescence with an anti-spike protein antibody, all the three neural cell lines were observed to be highly restrictive to the replication of the infecting virus. While the U87-MG glioblastoma cells demonstrated no cytopathic effects and a low viral titre with no signs of replication, the SHSY5Y neuroblastoma cells exhibited cytopathic effects with bleb formation but no evidence of viable virus. The C20 microglial cells showed neither signs of cytopathic effects nor viable virus. Ultrastructural studies demonstrated intracellular virions in infected neural cells. The presence of lipid droplets in infected SHSY5Y cells suggested an impact on host cell metabolism. The decrease in viral RNA levels over time in all the neural cell lines suggested restricted viral replication. In conclusion, this study highlights the limited susceptibility of neural cells to SARS-CoV-2 infection. This reduced permissibility of neural cell lines to SARS-CoV-2 may point to their inherent lower expression of receptors that support viral entry in addition to the intracellular factors that potently inhibit viral replication. The study findings prompt further investigation into the mechanisms of SARS-CoV-2 infection of neural cells.
Identifiants
pubmed: 38976047
doi: 10.1007/s00203-024-04075-4
pii: 10.1007/s00203-024-04075-4
doi:
Substances chimiques
Spike Glycoprotein, Coronavirus
0
RNA, Viral
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
345Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Andrews MG, Mukhtar T, Eze UC, Simoneau CR, Ross J, Parikshak N, Wang S, Zhou L, Koontz M, Velmeshev D, Siebert C-V, Gemenes KM, Tabata T, Perez Y, Wang L, Mostajo-Radji MA, de Majo M, Donohue KC, Shin D, Salma J, Pollen AA, Nowakowski TJ, Ullian E, Kumar GR, Winkler EA, Crouch EE, Ott M, Kriegstein AR (2022) Tropism of SARS-CoV-2 for human cortical astrocytes. Proc Natl Acad Sci U S A 119:e2122236119. https://doi.org/10.1073/pnas.2122236119
doi: 10.1073/pnas.2122236119
pubmed: 35858406
pmcid: 9335272
Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ (2022) Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 399:2263–2264. https://doi.org/10.1016/S0140-6736(22)00941-2
doi: 10.1016/S0140-6736(22)00941-2
pubmed: 35717982
pmcid: 9212672
Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, Glaser A, Elsayegh D (2020) COVID-19 presenting as stroke. Brain Behav Immun 87:115–119. https://doi.org/10.1016/j.bbi.2020.04.077
doi: 10.1016/j.bbi.2020.04.077
pubmed: 32360439
pmcid: 7187846
Baer A, Kehn-Hall K (2014) Viral concentration determination through plaque assays: using traditional and novel overlay systems. J Vis Exp JoVE 52065. https://doi.org/10.3791/52065
Bauer L, Rissmann M, Benavides FFW, Leijten L, van Run P, Begeman L, Veldhuis Kroeze EJB, Lendemeijer B, Smeenk H, de Vrij FMS, Kushner SA, Koopmans MPG, Rockx B, van Riel D (2022) In vitro and in vivo differences in neurovirulence between D614G, Delta and Omicron BA.1 SARS-CoV-2 variants. Acta Neuropathol Commun 10:124. https://doi.org/10.1186/s40478-022-01426-4
doi: 10.1186/s40478-022-01426-4
pubmed: 36058935
pmcid: 9441226
Bielarz V, Willemart K, Avalosse N, De Swert K, Lotfi R, Lejeune N, Poulain F, Ninanne N, Gilloteaux J, Gillet N, Nicaise C (2021) Susceptibility of neuroblastoma and glioblastoma cell lines to SARS-CoV-2 infection. Brain Res 1758:147344. https://doi.org/10.1016/j.brainres.2021.147344
doi: 10.1016/j.brainres.2021.147344
pubmed: 33556379
pmcid: 7863753
Cervia-Hasler C, Brüningk SC, Hoch T, Fan B, Muzio G, Thompson RC, Ceglarek L, Meledin R, Westermann P, Emmenegger M, Taeschler P, Zurbuchen Y, Pons M, Menges D, Ballouz T, Cervia-Hasler S, Adamo S, Merad M, Charney AW, Puhan M, Brodin P, Nilsson J, Aguzzi A, Raeber ME, Messner CB, Beckmann ND, Borgwardt K, Boyman O (2024) Persistent complement dysregulation with signs of thromboinflammation in active long covid. Science 383:eadg7942. https://doi.org/10.1126/science.adg7942
doi: 10.1126/science.adg7942
pubmed: 38236961
Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, Vinhas BS, Frisan T, Végvári Á, Mirazimi A, Neogi U, Gupta S (2021) Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells. Cell Death Discov 7:1–15. https://doi.org/10.1038/s41420-021-00487-z
doi: 10.1038/s41420-021-00487-z
Davis HE, McCorkell L, Vogel JM, Topol EJ (2023) Author correction: long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 21:408. https://doi.org/10.1038/s41579-023-00896-0
doi: 10.1038/s41579-023-00896-0
pubmed: 37069455
pmcid: 10408714
Eymieux S, Rouillé Y, Terrier O, Seron K, Blanchard E, Rosa-Calatrava M, Dubuisson J, Belouzard S, Roingeard P (2021) Ultrastructural modifications induced by SARS-CoV-2 in Vero cells: a kinetic analysis of viral factory formation, viral particle morphogenesis and virion release. Cell Mol Life Sci CMLS 78:3565–3576. https://doi.org/10.1007/s00018-020-03745-y
doi: 10.1007/s00018-020-03745-y
pubmed: 33449149
Gaussen A, Hornby L, Rockl G, O’Brien S, Delage G, Sapir-Pichhadze R, Drews SJ, Weiss MJ, Lewin A (2021) Evidence of SARS-CoV-2 infection in cells, tissues, and organs and the risk of transmission through transplantation. Transplantation 105:1405–1422. https://doi.org/10.1097/TP.0000000000003744
doi: 10.1097/TP.0000000000003744
pubmed: 33724248
Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci Lond Engl 1979 121:367–387. https://doi.org/10.1042/CS20110164
doi: 10.1042/CS20110164
Herrera-Moro Huitron L, De Jesús-González LA, Martínez-Castillo M, Ulloa-Aguilar JM, Cabello-Gutierrez C, Helguera-Repetto C, Garcia-Cordero J, León Juárez M (2023) Multifaceted nature of lipid droplets in viral interactions and Pathogenesis. Microorganisms 11:1851. https://doi.org/10.3390/microorganisms11071851
doi: 10.3390/microorganisms11071851
pubmed: 37513023
pmcid: 10386712
Jacob F, Pather SR, Huang W-K, Zhang F, Wong SZH, Zhou H, Cubitt B, Fan W, Chen CZ, Xu M, Pradhan M, Zhang DY, Zheng W, Bang AG, Song H, Carlos, de la Torre J, Ming G-L (2020) Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium. Cell Stem Cell 27:937–950.e9. https://doi.org/10.1016/j.stem.2020.09.016
Kim Y, Bae S, Chang H-H, Kim S-W (2023) Long COVID prevalence and impact on quality of life 2 years after acute COVID-19. Sci Rep 13:11207. https://doi.org/10.1038/s41598-023-36995-4
doi: 10.1038/s41598-023-36995-4
pubmed: 37433819
pmcid: 10336045
Kulkarni R, Gupta D, Pujari S, Deshpande V, Naphade P, Deshpande R (2022) Neurological manifestations in COVID-19 in three waves of the pandemic: an Inpatient Study from India. Ann Indian Acad Neurol 25:1047–1055. https://doi.org/10.4103/aian.aian_204_22
doi: 10.4103/aian.aian_204_22
pubmed: 36911448
pmcid: 9996479
Kumar N, Santhoshkumar R, Prasad P, George AK, Aiyar J, Joshi S, Narayanappa G, Desai AS, Ravi V, Venkataswamy MM (2023) An ultrastructural and genomic study on the SARS-CoV-2 variant B.1.210 circulating during the first wave of COVID-19 pandemic in India. Indian J Med Microbiol 41:45–52. https://doi.org/10.1016/j.ijmmb.2022.12.009
doi: 10.1016/j.ijmmb.2022.12.009
pubmed: 36870749
pmcid: 9822079
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B (2020) Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol 77:683–690. https://doi.org/10.1001/jamaneurol.2020.1127
doi: 10.1001/jamaneurol.2020.1127
pubmed: 32275288
Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shimada S (2020) A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis IJID off Publ Int Soc Infect Dis 94:55–58. https://doi.org/10.1016/j.ijid.2020.03.062
doi: 10.1016/j.ijid.2020.03.062
Muus C, Luecken MD, Eraslan G, Sikkema L, Waghray A, Heimberg G, Kobayashi Y, Vaishnav ED, Subramanian A, Smillie C, Jagadeesh KA, Duong ET, Fiskin E, Torlai Triglia E, Ansari M, Cai P, Lin B, Buchanan J, Chen S, Shu J, Haber AL, Chung H, Montoro DT, Adams T, Aliee H, Allon SJ, Andrusivova Z, Angelidis I, Ashenberg O, Bassler K, Bécavin C, Benhar I, Bergenstråhle J, Bergenstråhle L, Bolt L, Braun E, Bui LT, Callori S, Chaffin M, Chichelnitskiy E, Chiou J, Conlon TM, Cuoco MS, Cuomo ASE, Deprez M, Duclos G, Fine D, Fischer DS, Ghazanfar S, Gillich A, Giotti B, Gould J, Guo M, Gutierrez AJ, Habermann AC, Harvey T, He P, Hou X, Hu L, Hu Y, Jaiswal A, Ji L, Jiang P, Kapellos TS, Kuo CS, Larsson L, Leney-Greene MA, Lim K, Litviňuková M, Ludwig LS, Lukassen S, Luo W, Maatz H, Madissoon E, Mamanova L, Manakongtreecheep K, Leroy S, Mayr CH, Mbano IM, McAdams AM, Nabhan AN, Nyquist SK, Penland L, Poirion OB, Poli S, Qi C, Queen R, Reichart D, Rosas I, Schupp JC, Shea CV, Shi X, Sinha R, Sit RV, Slowikowski K, Slyper M, Smith NP, Sountoulidis A, Strunz M, Sullivan TB, Sun D, Talavera-López C, Tan P, Tantivit J, Travaglini KJ, Tucker NR, Vernon KA, Wadsworth MH, Waldman J, Wang X, Xu K, Yan W, Zhao W, Ziegler CGK NHLBI LungMap Consortium, Human Cell Atlas Lung Biological Network (2021) single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med 27:546–559. https://doi.org/10.1038/s41591-020-01227-z
Nardacci R, Colavita F, Castilletti C, Lapa D, Matusali G, Meschi S, Del Nonno F, Colombo D, Capobianchi MR, Zumla A, Ippolito G, Piacentini M, Falasca L (2021) Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis. Cell Death Dis 12:263. https://doi.org/10.1038/s41419-021-03527-9
doi: 10.1038/s41419-021-03527-9
pubmed: 33712574
pmcid: 7952828
Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fifi JT (2020) Large-vessel stroke as a presenting feature of Covid-19 in the Young. N Engl J Med 382:e60. https://doi.org/10.1056/NEJMc2009787
doi: 10.1056/NEJMc2009787
pubmed: 32343504
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B (2020) COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: imaging features. Radiology 296:E119–E120. https://doi.org/10.1148/radiol.2020201187
doi: 10.1148/radiol.2020201187
pubmed: 32228363
Qadri SW, Kumar N, Santhoshkumar R, Desai A, Ravi V, Venkataswamy MM (2022) Infection of human microglial cell line CHME-3 to study neuropathogenesis of Chikungunya virus. J Neurovirol. https://doi.org/10.1007/s13365-022-01070-7
doi: 10.1007/s13365-022-01070-7
pubmed: 35352315
Qiao J, Li W, Bao J, Peng Q, Wen D, Wang J, Sun B (2020) The expression of SARS-CoV-2 receptor ACE2 and CD147, and protease TMPRSS2 in human and mouse brain cells and mouse brain tissues. Biochem Biophys Res Commun 533:867–871. https://doi.org/10.1016/j.bbrc.2020.09.042
doi: 10.1016/j.bbrc.2020.09.042
pubmed: 33008593
pmcid: 7489930
Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, Meydan C, Park J, Foox J, Hether T, Warren S, Kim Y, Reeves J, Salvatore S, Mason CE, Swanson EC, Borczuk AC, Elemento O, Schwartz RE (2021) The spatial landscape of lung pathology during COVID-19 progression. Nature 593:564–569. https://doi.org/10.1038/s41586-021-03475-6
doi: 10.1038/s41586-021-03475-6
pubmed: 33780969
pmcid: 8204801
Romero-Sánchez CM, Díaz-Maroto I, Fernández-Díaz E, Sánchez-Larsen Á, Layos-Romero A, García-García J, González E, Redondo-Peñas I, Perona-Moratalla AB, Del Valle-Pérez JA, Gracia-Gil J, Rojas-Bartolomé L, Feria-Vilar I, Monteagudo M, Palao M, Palazón-García E, Alcahut-Rodríguez C, Sopelana-Garay D, Moreno Y, Ahmad J, Segura T (2020) Neurologic manifestations in hospitalized patients with COVID-19: the ALBACOVID registry. Neurology 95:e1060–e1070. https://doi.org/10.1212/WNL.0000000000009937
doi: 10.1212/WNL.0000000000009937
pubmed: 32482845
pmcid: 7668545
Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, Coyne C, Silvestri R, Golden N, Hensley K, Chandler K, Lehmicke G, Bix GJ, Maness NJ, Russell-Lodrigue K, Hu TY, Roy CJ, Blair RV, Bohm R, Doyle-Meyers LA, Rappaport J, Fischer T (2022) Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun 13:1745. https://doi.org/10.1038/s41467-022-29440-z
doi: 10.1038/s41467-022-29440-z
pubmed: 35365631
pmcid: 8975902
Sullivan BN, Fischer T (2021) Age-Associated Neurological complications of COVID-19: a systematic review and Meta-analysis. Front Aging Neurosci 13:653694. https://doi.org/10.3389/fnagi.2021.653694
doi: 10.3389/fnagi.2021.653694
pubmed: 34408638
pmcid: 8366271
Sureshbabu S, Joseph M, Haseena CV, Basheer N, Srutha Keerthi RN, Samrooda N, Abdurehiman KP, Deepthi PV, Peter B, Alappat J (2022) Comparison of neurological manifestations in the two waves of COVID-19 infection: a cross-sectional study. Ann Indian Acad Neurol 25:864–868. https://doi.org/10.4103/aian.aian_1048_21
doi: 10.4103/aian.aian_1048_21
pubmed: 36561032
pmcid: 9764885
Yang R, Huang B, Li AR, Wang W, Deng W, Tan Y W (2020) Development and effectiveness of pseudotyped SARS-CoV-2 system as determined by neutralizing efficiency and entry inhibition test in vitro. Biosaf Health 2:226–231. https://doi.org/10.1016/j.bsheal.2020.08.004
doi: 10.1016/j.bsheal.2020.08.004
pubmed: 32864605
pmcid: 7442068
Zhang Z, He G, Filipowicz NA, Randall G, Belov GA, Kopek BG, Wang X (2019) Host lipids in positive-strand RNA virus genome replication. Front Microbiol 10:286. https://doi.org/10.3389/fmicb.2019.00286
doi: 10.3389/fmicb.2019.00286
pubmed: 30863375
pmcid: 6399474
Zhang B-Z, Chu H, Han S, Shuai H, Deng J, Hu Y-F, Gong H-R, Lee AC-Y, Zou Z, Yau T, Wu W, Hung IF-N, Chan JF-W, Yuen K-Y, Huang J-D (2020) SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res 30:928–931. https://doi.org/10.1038/s41422-020-0390-x
doi: 10.1038/s41422-020-0390-x
pubmed: 32753756