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A suitable model to investigate acute neurological consequences of coronavirus infection

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Abstract

Objective and design

The present study aimed to investigate the neurochemical and behavioral effects of the acute consequences after coronavirus infection through a murine model.

Material

Wild-type C57BL/6 mice were infected intranasally (i.n) with the murine coronavirus 3 (MHV-3). Methods: Mice underwent behavioral tests. Euthanasia was performed on the fifth day after infection (5 dpi), and the brain tissue was subjected to plaque assays for viral titration, ELISA, histopathological, immunohistochemical and synaptosome analysis. Results: Increased viral titers and mild histological changes, including signs of neuronal degeneration, were observed in the cerebral cortex of infected mice. Importantly, MHV-3 infection induced an increase in cortical levels of glutamate and calcium, which is indicative of excitotoxicity, as well as increased levels of pro-inflammatory cytokines (IL-6, IFN-γ) and reduced levels of neuroprotective mediators (BDNF and CX3CL1) in the mice brain. Finally, behavioral analysis showed impaired motor, anhedonia-like and anxiety-like behaviors in animals infected with MHV-3.

Conclusions

In conclusion, the data presented emulate many aspects of the acute neurological outcomes seen in patients with COVID-19. Therefore, this model may provide a preclinical platform to study acute neurological sequelae induced by coronavirus infection and test possible therapies.

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Data availability

The data that support the findings of this study are included within the article and available if required.

References

  1. Bougakov D, Podell K, Goldberg E. Multiple neuroinvasive pathways in COVID-19. Mol Neurobiol. 2021;58(2):564–75. https://doi.org/10.1007/s12035-020-02152-5.

    Article  CAS  PubMed  Google Scholar 

  2. Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol. 2021;268(9):3059–71. https://doi.org/10.1007/s00415-021-10406-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, Dottermusch M, Heinemann A, Pfefferle S, Schwabenland M, Sumner Magruder D, Bonn S, Prinz M, Gerloff C, Püschel K, Glatzel M. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19(11):919–29. https://doi.org/10.1016/S1474-4422(20)30308-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, Laue M, Schneider J, Brünink S, Greuel S, Lehmann M, Hassan O, Aschman T, Schumann E, Chua RL, Conrad C, Eils R, Stenzel W, Windgassen M, Heppner FL. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24(2):168–75. https://doi.org/10.1038/s41593-020-00758-5.

    Article  CAS  PubMed  Google Scholar 

  5. Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, Braun F, Lu S, Pfefferle S, Schröder AS, Edler C, Gross O, Glatzel M, Wichmann D, Wiech T, Huber TB. Multiorgan and renal tropism of SARS-CoV-2. New Engld J Med. 2020;383(6):590–2. https://doi.org/10.1056/NEJMc2011400.

    Article  Google Scholar 

  6. Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman O-E, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Iwasaki A. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Experim Med. 2021. https://doi.org/10.1084/jem.20202135.

    Article  Google Scholar 

  7. Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, Appelt-Menzel A, Cubukova A, Barenberg J, Leu J, Hartmann K, Thies E, Littau JL, Sepulveda-Falla D, Zhang L, Ton K, Liang Y, Matschke J, Ricklefs F, Pless O. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022;17(2):307–20. https://doi.org/10.1016/j.stemcr.2021.12.011.

    Article  CAS  Google Scholar 

  8. Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiat. 2021;78(6):682. https://doi.org/10.1001/jamapsychiatry.2021.0500.

    Article  Google Scholar 

  9. Burks SM, Rosas-Hernandez H, Alejandro Ramirez-Lee M, Cuevas E, Talpos JC. Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier? Brain Behav Immun. 2021;95:7–14. https://doi.org/10.1016/j.bbi.2020.12.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Perlman S, Evans G, Afifi A. Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain. J Exp Med. 1990;172(4):1127–32. https://doi.org/10.1084/jem.172.4.1127.

    Article  CAS  PubMed  Google Scholar 

  11. Cowley TJ, Weiss SR. Murine coronavirus neuropathogenesis: determinants of virulence. J Neurovirol. 2010;16(6):427–34. https://doi.org/10.1007/BF03210848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheng Q, Yang Y, Gao J. Infectivity of human coronavirus in the brain. EBioMedicine. 2020;56:102799. https://doi.org/10.1016/j.ebiom.2020.102799.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Andrade AC, dos SP, Campolina-Silva GH, Queiroz-Junior CM, de Oliveira LC, Lacerda L de SB, Gaggino JCP, de Souza FRO, de Meira Chaves I, Passos IB, Teixeira DC, Bittencourt-Silva PG, Valadão PAC, Rossi-Oliveira L, Antunes MM, Figueiredo AFA, Wnuk NT, Temerozo JR, Ferreira AC, Cramer A, Costa VV (2021) A biosafety level 2 mouse model for studying betacoronavirus-induced acute lung damage and systemic manifestations. J Virol https://doi.org/10.1128/JVI.01276-21

  14. Reza-Zaldívar EE, Hernández-Sapiéns MA, Minjarez B, Gómez-Pinedo U, Márquez-Aguirre AL, Mateos-Díaz JC, Matias-Guiu J, Canales-Aguirre AA. Infection mechanism of SARS-COV-2 and its implication on the nervous system. Front Immunol. 2021. https://doi.org/10.3389/fimmu.2020.621735.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Weiss SR, Leibowitz JL (2011) Coronavirus Pathogenesis (pp. 85–164). https://doi.org/10.1016/B978-0-12-385885-6.00009-2

  16. Garcia AB, de Moraes AP, Rodrigues DM, Gilioli R, de Oliveira-Filho EF, Durães-Carvalho R, Arns CW. Coding-complete genome sequence of murine hepatitis virus strain 3 from Brazil. Microbiol Resour Announc. 2021. https://doi.org/10.1128/MRA.00248-21.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Amaral DC, Rachid MA, Vilela MC, Campos RD, Ferreira GP, Rodrigues DH, Lacerda-Queiroz N, Miranda AS, Costa VV, Campos MA, Kroon EG, Teixeira MM, Teixeira AL. Intracerebral infection with dengue-3 virus induces meningoencephalitis and behavioral changes that precede lethality in mice. J Neuroinflamm. 2011;8(1):23. https://doi.org/10.1186/1742-2094-8-23.

    Article  Google Scholar 

  18. Costa VV, Del Sarto JL, Rocha RF, Silva FR, Doria JG, Olmo IG, Marques RE, Queiroz-Junior CM, Foureaux G, Araújo JMS, Cramer A, Real ALCV, Ribeiro LS, Sardi SI, Ferreira AJ, Machado FS, de Oliveira AC, Teixeira AL, Nakaya HI, Teixeira MM. N -Methyl-d-Aspartate (NMDA) receptor blockade prevents neuronal death induced by Zika virus infection. MBio. 2017. https://doi.org/10.1128/mBio.00350-17.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dunkley PR, Heath JW, Harrison SM, Jarvie PE, Glenfield PJ, Rostas JAP. A rapid Percoll gradient procedure for isolation of synaptosomes directly from an S1 fraction: homogeneity and morphology of subcellular fractions. Brain Res. 1988;441(1–2):59–71. https://doi.org/10.1016/0006-8993(88)91383-2.

    Article  CAS  PubMed  Google Scholar 

  20. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985;260(6):3440–50.

    Article  CAS  PubMed  Google Scholar 

  21. Nicholls DG, Sihra TS, Sanchez-Prieto J. Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J Neurochem. 1987;49(1):50–7. https://doi.org/10.1111/j.1471-4159.1987.tb03393.x.

    Article  CAS  PubMed  Google Scholar 

  22. Rodrigues HA, de Fonseca MC, Camargo WL, Lima PMA, Martinelli PM, Naves LA, Prado VF, Prado MAM, Guatimosim C. Reduced expression of the vesicular acetylcholine transporter and neurotransmitter content affects synaptic vesicle distribution and shape in mouse neuromuscular junction. PLoS One. 2013;8(11): e78342. https://doi.org/10.1371/journal.pone.0078342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A. Amyloid β, glutamate, excitotoxicity in Alzheimer’s Disease: are we on the right track? CNS Neurosci Ther. 2013;19(8):549–55. https://doi.org/10.1111/cns.12095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mody I. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol Sci. 1995;16(10):356–9. https://doi.org/10.1016/S0165-6147(00)89070-7.

    Article  CAS  PubMed  Google Scholar 

  25. Prediger RDS, Aguiar AS, Rojas-Mayorquin AE, Figueiredo CP, Matheus FC, Ginestet L, Chevarin C, Bel ED, Mongeau R, Hamon M, Lanfumey L, Raisman-Vozari R. Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson’s disease. Neurotox Res. 2010;17(2):114–29. https://doi.org/10.1007/s12640-009-9087-0.

    Article  CAS  PubMed  Google Scholar 

  26. Oliveira TPD, Gonçalves BDC, Oliveira BS, de Oliveira ACP, Reis HJ, Ferreira CN, Aguiar DC, de Miranda AS, Ribeiro FM, Vieira EML, Palotás A, Vieira LB. Negative modulation of the metabotropic glutamate receptor type 5 as a potential therapeutic strategy in obesity and binge-like eating behavior. Front Neurosci. 2021. https://doi.org/10.3389/fnins.2021.631311.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Camargos QM, Silva BC, Silva DG, Toscano ECB, Oliveira BS, Bellozi PMQ, Jardim BLO, Vieira ÉLM, de Oliveira ACP, Sousa LP, Teixeira AL, de Miranda AS, Rachid MA. Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke. Brain Res Bull. 2020;155:1–10. https://doi.org/10.1016/j.brainresbull.2019.11.009.

    Article  CAS  PubMed  Google Scholar 

  28. de Miranda AS, Brant F, Vieira LB, Rocha NP, Vieira ÉLM, Rezende GHS, de Oliveira Pimentel PM, Moraes MFD, Ribeiro FM, Ransohoff RM, Teixeira MM, Machado FS, Rachid MA, Teixeira AL. A neuroprotective effect of the glutamate receptor antagonist MK801 on long-term cognitive and behavioral outcomes secondary to experimental cerebral malaria. Mol Neurobiol. 2017;54(9):7063–82. https://doi.org/10.1007/s12035-016-0226-3.

    Article  CAS  PubMed  Google Scholar 

  29. Eltokhi A, Kurpiers B, Pitzer C. Baseline depression-like behaviors in wild-type adolescent mice are strain and age but not sex dependent. Front Behav Neurosci. 2021. https://doi.org/10.3389/fnbeh.2021.759574.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, Redfield S, Austin JP, Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021. https://doi.org/10.1016/j.eclinm.2021.101019.

    Article  PubMed  PubMed Central  Google Scholar 

  31. WHO Coronavirus (COVID-19) Dashboard. Available from: https://covid19.who.int/.

  32. Gorska AM, Eugenin EA. The glutamate system as a crucial regulator of CNS toxicity and survival of HIV reservoirs. Front Cell Infect Microbiol. 2020. https://doi.org/10.3389/fcimb.2020.00261.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Brison E, Jacomy H, Desforges M, Talbot PJ. Glutamate excitotoxicity is involved in the induction of paralysis in mice after infection by a human coronavirus with a single point mutation in its spike protein. J Virol. 2011;85(23):12464–73. https://doi.org/10.1128/JVI.05576-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu GJ, Nagarajah R, Banati RB, Bennett MR. Glutamate induces directed chemotaxis of microglia. Eur J Neurosci. 2009;29(6):1108–18. https://doi.org/10.1111/j.1460-9568.2009.06659.x.

    Article  PubMed  Google Scholar 

  35. Sanchis P, Fernández-Gayol O, Comes G, Escrig A, Giralt M, Palmiter RD, Hidalgo J. Interleukin-6 derived from the central nervous system may influence the pathogenesis of experimental autoimmune encephalomyelitis in a cell-dependent manner. Cells. 2020;9(2):330. https://doi.org/10.3390/cells9020330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sallmann S, Jüttler E, Prinz S, Petersen N, Knopf U, Weiser T, Schwaninger M. Induction of interleukin-6 by depolarization of neurons. J Neurosci. 2000;20(23):8637–42. https://doi.org/10.1523/JNEUROSCI.20-23-08637.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lotrich FE. Inflammatory cytokine-associated depression. Brain Res. 2015;1617:113–25. https://doi.org/10.1016/j.brainres.2014.06.032.

    Article  CAS  PubMed  Google Scholar 

  38. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL. A meta-analysis of cytokines in major depression. Biol Psychiat. 2010;67(5):446–57. https://doi.org/10.1016/j.biopsych.2009.09.033.

    Article  CAS  PubMed  Google Scholar 

  39. Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci. 2007;8(3):221–32. https://doi.org/10.1038/nrn2054.

    Article  CAS  PubMed  Google Scholar 

  40. Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42(1):193–215. https://doi.org/10.1038/npp.2016.199.

    Article  CAS  PubMed  Google Scholar 

  41. Lauro C, Catalano M, Di Paolo E, Chece G, de Costanzo I, Trettel F, Limatola C. Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation. Front Cell Neurosci. 2015. https://doi.org/10.3389/fncel.2014.00472.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Binder GK, Griffin DE. Interferon-γ-mediated site-specific clearance of alphavirus from CNS neurons. Science. 2001;293(5528):303–6. https://doi.org/10.1126/science.1059742.

    Article  CAS  PubMed  Google Scholar 

  43. Ganor Y, Besser M, Ben-Zakay N, Unger T, Levite M. Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. J Immunol. 2003;170(8):4362–72. https://doi.org/10.4049/jimmunol.170.8.4362.

    Article  CAS  PubMed  Google Scholar 

  44. Miyanishi H, Nitta A. A role of BDNF in the depression pathogenesis and a potential target as antidepressant: The modulator of stress sensitivity “Shati/Nat8l-BDNF system” in the dorsal striatum. Pharmaceuticals. 2021;14(9):889. https://doi.org/10.3390/ph14090889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li H, Wang T, Shi C, Yang Y, Li X, Wu Y, Xu Z-QD. Inhibition of GALR1 in PFC alleviates depressive-like behaviors in postpartum depression rat model by upregulating CREB-BNDF and 5-HT levels. Front Psychiatry. 2018. https://doi.org/10.3389/fpsyt.2018.00588.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li M, Li C, Yu H, Cai X, Shen X, Sun X, Wang J, Zhang Y, Wang C. Lentivirus-mediated interleukin-1β (IL-1β) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice. J Neuroinflammation. 2017;14(1):190. https://doi.org/10.1186/s12974-017-0964-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cirulli F, Berry A, Chiarotti F, Alleva E. Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus. 2004;14(7):802–7. https://doi.org/10.1002/hipo.10220.

    Article  CAS  PubMed  Google Scholar 

  48. Chamera K, Trojan E, Szuster-Głuszczak M, Basta-Kaim A. The potential role of dysfunctions in neuron-microglia communication in the pathogenesis of brain disorders. Curr Neuropharmacol. 2020;18(5):408–30. https://doi.org/10.2174/1570159X17666191113101629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Marcolino MS, Anschau F, Kopittke L, Pires MC, Barbosa IG, Pereira DN, Ramos LEF, Assunção LFI, Costa ASM, Nogueira MCA, Duani H, Martins KPMP, Moreira LB, Silva CTCA, Oliveira NR, de Ziegelmann PK, Guimarães-Júnior MH, Lima MOSS, Aguiar RLO, Teixeira AL. Frequency and burden of neurological manifestations upon hospital presentation in COVID-19 patients: Findings from a large Brazilian cohort. J Neurol Sci. 2022. https://doi.org/10.1016/j.jns.2022.120485.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pereira DN, Bicalho MAC, Jorge AO, Gomes AGR, Schwarzbold AV, Araújo ALH, Cimini CCR, Ponce D, Rios DRA, Grizende GMS, Manenti ERF, Anschau F, Aranha FG, Bartolazzi F, Batista JL, Tupinambás JT, Ruschel KB, Ferreira MAP, Paraíso PG, Marcolino MS. Neurological manifestations by sex and age group in COVID-19 inhospital patients. ENeurologicalSci. 2022;28:100419. https://doi.org/10.1016/j.ensci.2022.100419.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Chou SH-Y, Beghi E, Helbok R, Moro E, Sampson J, Altamirano V, Mainali S, Bassetti C, Suarez JI, McNett M, Nolan L, Temro K, Cervantes-Arslanian AM, Anand P, Mukerji S, Alabasi H, Westover MB, Kavi T, John S, David K. Global incidence of neurological manifestations among patients hospitalized with COVID-19—a report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. JAMA Network Open. 2021;4(5):e2112131. https://doi.org/10.1001/jamanetworkopen.2021.12131.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, Adams G, Hornick JL, Padera RF, Sabeti P. Neuropathological features of Covid-19. N Engl J Med. 2020;383(10):989–92. https://doi.org/10.1056/NEJMc2019373.

    Article  PubMed  Google Scholar 

  53. Boroujeni ME, Simani L, Bluyssen HAR, Samadikhah HR, Zamanlui Benisi S, Hassani S, Akbari Dilmaghani N, Fathi M, Vakili K, Mahmoudiasl G-R, Abbaszadeh HA, Hassani Moghaddam M, Abdollahifar M-A, Aliaghaei A. Inflammatory response leads to neuronal death in human post-mortem cerebral cortex in patients with COVID-19. ACS Chem Neurosci. 2021;12(12):2143–50. https://doi.org/10.1021/acschemneuro.1c00111.

    Article  CAS  PubMed  Google Scholar 

  54. Csordás A, Mázló M, Gallyas F. Recovery versus death of “dark” (compacted) neurons in non-impaired parenchymal environment: light and electron microscopic observations. Acta Neuropathol. 2003;106(1):37–49. https://doi.org/10.1007/s00401-003-0694-1.

    Article  PubMed  Google Scholar 

  55. de Miranda AS, Rodrigues DH, Amaral DCG, de Lima Campos RD, Cisalpino D, Vilela MC, Lacerda-Queiroz N, de Souza KPR, Vago JP, Campos MA, Kroon EG. Dengue-3 encephalitis promotes anxiety-like behavior in mice. Behav Brain Res. 2012;230(1):237–42. https://doi.org/10.1016/j.bbr.2012.02.020.

    Article  CAS  PubMed  Google Scholar 

  56. 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, Kriegstein AR. Tropism of SARS-CoV-2 for human cortical astrocytes. Proc Natl Acad Sci. 2022. https://doi.org/10.1073/pnas.2122236119.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Winkler ES, Bailey AL, Kafai NM, Nair S, McCune BT, Yu J, Fox JM, Chen RE, Earnest JT, Keeler SP, Ritter JH, Kang L-I, Dort S, Robichaud A, Head R, Holtzman MJ, Diamond MS. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020;21(11):1327–35. https://doi.org/10.1038/s41590-020-0778-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kumari P, Rothan HA, Natekar JP, Stone S, Pathak H, Strate PG, Arora K, Brinton MA, Kumar M. Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice. Viruses. 2021;13(1):132. https://doi.org/10.3390/v13010132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu N-H, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8. https://doi.org/10.1016/j.cell.2020.02.052.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Düsedau HP, Steffen J, Figueiredo CA, Boehme JD, Schultz K, Erck C, Korte M, Faber-Zuschratter H, Smalla K-H, Dieterich D, Kröger A, Bruder D, Dunay IR. Influenza A Virus (H1N1) infection induces microglial activation and temporal dysbalance in glutamatergic synaptic transmission. MBio. 2021. https://doi.org/10.1128/mBio.01776-21.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Olmo IG, Carvalho TG, Costa VV, Alves-Silva J, Ferrari CZ, Izidoro-Toledo TC, da Silva JF, Teixeira AL, Souza DG, Marques JT, Teixeira MM, Vieira LB, Ribeiro FM. Zika virus promotes neuronal cell death in a non-cell autonomous manner by triggering the release of neurotoxic factors. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.01016.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Oladunni FS, Park JG, Pino PA, Gonzalez O, Akhter A, Allué-Guardia A, Olmo-Fontánez A, Gautam S, Garcia-Vilanova A, Ye C, Chiem K, Headley C, Dwivedi V, Parodi LM, Alfson KJ, Staples HM, Schami A, Garcia JI, Whigham A, Torrelles JB. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nat Commun. 2020;11(1):6122. https://doi.org/10.1038/s41467-020-19891-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rothan H, Kumari P, Stone S, Natekar J, Arora K, Auroni T, Kumar M. SARS-CoV-2 infects primary neurons from human ACE2 expressing mice and upregulates genes involved in the inflammatory and necroptotic pathways. Pathogens. 2022;11(2):257. https://doi.org/10.3390/pathogens11020257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Vieira-Alves I, Alves ARP, Souza NMV, Melo TL, Coimbra Campos LMC, Lacerda LSB, Queiroz-Junior CM, Andrade ACSP, Barcelos LS, Teixeira MM, Costa VV, Cortes SF, Lemos VS. TNF/iNOS/NO pathway mediates host susceptibility to endothelial-dependent circulatory failure and death induced by betacoronavirus infection. Clin Sci. 2023;137(7):543–59. https://doi.org/10.1042/CS20220663.

    Article  CAS  Google Scholar 

  65. Heap RE, Marín-Rubio JL, Peltier J, Heunis T, Dannoura A, Moore A, Trost M (2021) Proteomics characterisation of the L929 cell supernatant and its role in BMDM differentiation. Life Sci Alliance 4(6): e202000957. https://doi.org/10.26508/lsa.202000957

  66. Costa AP, Vieira C, Bohner LO, Silva CF, Santos EC, De Lima TC, Lino-de-Oliveira C. A proposal for refining the forced swim test in Swiss mice. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:150–5. https://doi.org/10.1016/j.pnpbp.2013.05.002.

    Article  PubMed  Google Scholar 

  67. Suman P, Zerbinatti N, Theindl L, Domingues K, Lino de Oliveira C. Failure to detect the action of antidepressants in the forced swim test in Swiss mice. Acta Neuropsychiatrica. 2018;30(3):158–67. https://doi.org/10.1017/neu.2017.33.

    Article  PubMed  Google Scholar 

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This study was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior,88881.507175 /2020 -01, Fundação de Amparo à Pesquisa do Estado de Minas Gerais,APQ 02281-18,APQ 02281-18, Conselho Nacional de Desenvolvimento Científico e Tecnológico,465425 /2014-3

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Author notes

  1. Jordane Pimenta and Bruna Da Silva Oliveira authors contributed equally to this work.

Authors and Affiliations

  1. Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos, 6627, Belo Horizonte, MG, 31270-901, Brazil

    Jordane Pimenta, Bruna Da Silva Oliveira, Caroline Amaral Machado, Larisse De Souza Barbosa Lacerda, Leonardo Rossi, Celso Martins Queiroz-Junior, Ana Claudia Santos Pereira Andrade, Bárbara Mota, Cristina Guatimosim, Aline Silva De Miranda & Vivian Vasconcelos Costa

  2. Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Fernanda Martins Marim & Renato Santana Aguiar

  3. Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Anna Luiza Diniz Lima, Pedro Pires Goulart Guimarães & Luciene Bruno Vieira

  4. Department of Psychiatry and Behavioral Sciences, McGovern Medical Houston, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Antônio Lúcio Teixeira

  5. Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Luiz Pedro De Souza-Costa & Mauro Martins Teixeira

  6. Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Matheus Rodrigues Gonçalves

Authors
  1. Jordane Pimenta
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  2. Bruna Da Silva Oliveira
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  3. Anna Luiza Diniz Lima
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  4. Caroline Amaral Machado
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  5. Larisse De Souza Barbosa Lacerda
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  6. Leonardo Rossi
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  7. Celso Martins Queiroz-Junior
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  8. Luiz Pedro De Souza-Costa
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  9. Ana Claudia Santos Pereira Andrade
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  10. Matheus Rodrigues Gonçalves
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  11. Bárbara Mota
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  12. Fernanda Martins Marim
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  13. Renato Santana Aguiar
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  14. Pedro Pires Goulart Guimarães
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  15. Antônio Lúcio Teixeira
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  16. Luciene Bruno Vieira
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  17. Cristina Guatimosim
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  18. Mauro Martins Teixeira
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  19. Aline Silva De Miranda
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  20. Vivian Vasconcelos Costa
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Contributions

J.C. Pimenta: Conceptualization, Methodology, Investigation, Writing – Original Draft, Writing – Review & Editing, Project administration. B. D. S Oliveira: Investigation, Writing – Original Draft; A.L.D. Lima: Investigation, Methodology. C.A. Machado: Investigation. L. Rossi: Investigation, Writing – Original Draft- Review & Editing. L.D.S.B. Lacerda: Investigation. C.M. Queiroz-Junior: Investigation, Writing – Original Draft- Review & Editing. A.C. D. S. P. Andrade: S.R. Oliveira: Conceptualization, Methodology. M.R. Gonçalves: Investigation. B. Mota: Investigator. F. M. Marim: Investigator- Review & Editing. R. Santana: Review & Editing. P. Pires: Resources. A. L. Teixeira: Writing -Review & Editing. L.B. Vieira: Writing - Review & Editing, Resources. C. Guatimosim: Writing – Review & Editing, Resources. M.M. Teixeira: Writing – Review & Editing, Resources, Project administration, Funding acquisition. A.S.D Miranda: Conceptualization, Methodology, Resources, Writing – Review & Editing, Project administration. V.V. Costa: Conceptualization, Methodology, Resources, Writing – Review & Editing, Supervision, Project administration, Funding acquisition.

Corresponding authors

Correspondence to Aline Silva De Miranda or Vivian Vasconcelos Costa.

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Pimenta, J., Da Silva Oliveira, B., Lima, A.L.D. et al. A suitable model to investigate acute neurological consequences of coronavirus infection. Inflamm. Res. 72, 2073–2088 (2023). https://doi.org/10.1007/s00011-023-01798-w

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