SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
24
01
2022
accepted:
07
10
2022
revised:
19
09
2022
medline:
1
11
2023
pubmed:
2
11
2022
entrez:
1
11
2022
Statut:
ppublish
Résumé
Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson's disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson's disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
Identifiants
pubmed: 36316366
doi: 10.1038/s41380-022-01831-0
pii: 10.1038/s41380-022-01831-0
pmc: PMC10615762
doi:
Substances chimiques
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
alpha-Synuclein
0
spike protein, SARS-CoV-2
0
Spike Glycoprotein, Coronavirus
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2878-2893Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 2009957
Informations de copyright
© 2022. The Author(s).
Références
Albornoz EA, Woodruff TM, Gordon R. Inflammasomes in CNS diseases. Exp Suppl. 2018;108:41–60.
pubmed: 30536167
Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019;11:e10248.
pubmed: 31015277
pmcid: 6554670
doi: 10.15252/emmm.201810248
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.
pubmed: 12191486
doi: 10.1016/S1097-2765(02)00599-3
Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018;10:eaah4066.
pubmed: 30381407
pmcid: 6483075
doi: 10.1126/scitranslmed.aah4066
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.
pubmed: 23254930
doi: 10.1038/nature11729
Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AAB, et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020;68:407–21.
pubmed: 31596526
doi: 10.1002/glia.23728
Kaushik DK, Gupta M, Kumawat KL, Basu A. NLRP3 inflammasome: key mediator of neuroinflammation in murine Japanese encephalitis. PLoS One. 2012;7:e32270.
pubmed: 22393394
pmcid: 3290554
doi: 10.1371/journal.pone.0032270
Wang W, Li G, De W, Luo Z, Pan P, Tian M, et al. Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1beta secretion. Nat Commun. 2018;9:106.
pubmed: 29317641
pmcid: 5760693
doi: 10.1038/s41467-017-02645-3
Ferini-Strambi L, Salsone M. COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable? J Neurol. 2021;268:409–19.
pubmed: 32696341
doi: 10.1007/s00415-020-10070-8
Liu J, Li Y, Liu Q, Yao Q, Wang X, Zhang H, et al. SARS-CoV-2 cell tropism and multiorgan infection. Cell Disco. 2021;7:17.
doi: 10.1038/s41421-021-00249-2
Puelles VG, Lutgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl J Med. 2020;383:590–2.
pubmed: 32402155
doi: 10.1056/NEJMc2011400
Thakur KT, Miller EH, Glendinning MD, Al-Dalahmah O, Banu MA, Boehme AK, et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain. 2021;144:2696–2708.
pubmed: 33856027
pmcid: 8083258
doi: 10.1093/brain/awab148
Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19:919–29.
pubmed: 33031735
pmcid: 7535629
doi: 10.1016/S1474-4422(20)30308-2
Seehusen F, Clark JJ, Sharma P, Bentley EG, Kirby A, Subramaniam K, et al. Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse. Viruses. 2022;14:1020.
pubmed: 35632761
pmcid: 9146514
doi: 10.3390/v14051020
Kaufer C, Schreiber CS, Hartke AS, Denden I, Stanelle-Bertram S, Beck S, et al. Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model. EBioMedicine. 2022;79:103999.
pubmed: 35439679
pmcid: 9013202
doi: 10.1016/j.ebiom.2022.103999
Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun. 2022;13:1745.
pubmed: 35365631
pmcid: 8975902
doi: 10.1038/s41467-022-29440-z
Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19:767–83.
pubmed: 32622375
pmcid: 7332267
doi: 10.1016/S1474-4422(20)30221-0
Merello M, Bhatia KP, Obeso JA. SARS-CoV-2 and the risk of Parkinson’s disease: facts and fantasy. Lancet Neurol. 2021;20:94–95.
pubmed: 33253627
doi: 10.1016/S1474-4422(20)30442-7
Najjar S, Najjar A, Chong DJ, Pramanik BK, Kirsch C, Kuzniecky RI, et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation. 2020;17:231.
pubmed: 32758257
pmcid: 7406702
doi: 10.1186/s12974-020-01896-0
Chen AK, Wang X, McCluskey LP, Morgan JC, Switzer JA, Mehta R, et al. Neuropsychiatric sequelae of long COVID-19: Pilot results from the COVID-19 neurological and molecular prospective cohort study in Georgia. Usa Brain Behav Immun Health. 2022;24:100491.
pubmed: 35873350
doi: 10.1016/j.bbih.2022.100491
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8:416–27.
pubmed: 33836148
pmcid: 8023694
doi: 10.1016/S2215-0366(21)00084-5
Siderowf A, Jennings D, Eberly S, Oakes D, Hawkins KA, Ascherio A, et al. Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study. Mov Disord. 2012;27:406–12.
pubmed: 22237833
pmcid: 6342466
doi: 10.1002/mds.24892
Cohen ME, Eichel R, Steiner-Birmanns B, Janah A, Ioshpa M, Bar-Shalom R, et al. A case of probable Parkinson’s disease after SARS-CoV-2 infection. Lancet Neurol. 2020;19:804–5.
pubmed: 32949534
pmcid: 7494295
doi: 10.1016/S1474-4422(20)30305-7
Mendez-Guerrero A, Laespada-Garcia MI, Gomez-Grande A, Ruiz-Ortiz M, Blanco-Palmero VA, Azcarate-Diaz FJ, et al. Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection. Neurology. 2020;95:e2109–e2118.
pubmed: 32641525
doi: 10.1212/WNL.0000000000010282
Faber I, Brandao PRP, Menegatti F, de Carvalho Bispo DD, Maluf FB, Cardoso F. Coronavirus disease 2019 and Parkinsonism: a non-post-encephalitic case. Mov Disord. 2020;35:1721–2.
pubmed: 32815213
pmcid: 7461093
doi: 10.1002/mds.28277
Pavel A, Murray DK, Stoessl AJ. COVID-19 and selective vulnerability to Parkinson’s disease. Lancet Neurol. 2020;19:719.
pubmed: 32822628
pmcid: 7434474
doi: 10.1016/S1474-4422(20)30269-6
Brundin P, Nath A, Beckham JD. Is COVID-19 a perfect storm for Parkinson’s disease? Trends Neurosci. 2020;43:931–3.
pubmed: 33158605
pmcid: 7577682
doi: 10.1016/j.tins.2020.10.009
Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020;583:830–3.
pubmed: 32380511
doi: 10.1038/s41586-020-2312-y
Isaacs A, Amarilla AA, Aguado J, Modhiran N, Albornoz EA, Baradar AA, et al. Nucleocapsid specific diagnostics for the detection of divergent SARS-CoV-2 variants. Front Immunol. 2022;13:926262.
pubmed: 35757714
pmcid: 9226548
doi: 10.3389/fimmu.2022.926262
Li XX, Clark RJ, Woodruff TM. C5aR2 activation broadly modulates the signaling and function of primary human macrophages. J Immunol. 2020;205:1102–12.
pubmed: 32611725
doi: 10.4049/jimmunol.2000407
Deora V, Albornoz EA, Zhu K, Woodruff TM, Gordon R. The ketone body beta-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia. J Neuroimmune Pharm. 2017;12:568–74.
doi: 10.1007/s11481-017-9754-5
Amarilla AA, Sng JDJ, Parry R, Deerain JM, Potter JR, Setoh YX, et al. A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses. Nat Commun. 2021;12:3431.
pubmed: 34103499
pmcid: 8187723
doi: 10.1038/s41467-021-23779-5
Grubaugh ND, Gangavarapu K, Quick J, Matteson NL, De Jesus JG, Main BJ, et al. An amplicon-based sequencing framework for accurately measuring intrahost virus diversity using PrimalSeq and iVar. Genome Biol. 2019;20:8.
pubmed: 30621750
pmcid: 6325816
doi: 10.1186/s13059-018-1618-7
Amarilla AA, Modhiran N, Setoh YX, Peng NYG, Sng JDJ, Liang B, et al. An optimized high-throughput immuno-plaque assay for SARS-CoV-2. Front Microbiol. 2021;12:625136.
pubmed: 33643253
pmcid: 7906992
doi: 10.3389/fmicb.2021.625136
CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel. https://www.cdc.gov/coronavirus/2019-ncov/lab/virus-requests.html , 2021, Accessed Date.
Conceicao C, Thakur N, Human S, Kelly JT, Logan L, Bialy D, et al. The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins. PLoS Biol. 2020;18:e3001016.
pubmed: 33347434
pmcid: 7751883
doi: 10.1371/journal.pbio.3001016
Watterson D, Wijesundara DK, Modhiran N, Mordant FL, Li Z, Avumegah MS, et al. Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2. Clin Transl Immunol. 2021;10:e1269.
doi: 10.1002/cti2.1269
Isaacs A, Cheung STM, Thakur N, Jaberolansar N, Young A, Modhiran N, et al. Combinatorial F-G immunogens as nipah and respiratory syncytial virus vaccine candidates. Viruses. 2021;13:1942.
pubmed: 34696372
pmcid: 8537613
doi: 10.3390/v13101942
ter Meulen J, van den Brink EN, Poon LL, Marissen WE, Leung CS, Cox F, et al. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLoS Med. 2006;3:e237.
pubmed: 16796401
pmcid: 1483912
doi: 10.1371/journal.pmed.0030237
Zheng J, Wong LR, Li K, Verma AK, Ortiz ME, Wohlford-Lenane C, et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature. 2021;589:603–7.
pubmed: 33166988
doi: 10.1038/s41586-020-2943-z
Ryan KJ, White CC, Patel K, Xu J, Olah M, Replogle JM, et al. A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci Transl Med. 2017;9:eaai7635.
pubmed: 29263232
pmcid: 5945290
doi: 10.1126/scitranslmed.aai7635
Yang J, Petitjean SJL, Koehler M, Zhang Q, Dumitru AC, Chen W, et al. Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor. Nat Commun. 2020;11:4541.
pubmed: 32917884
pmcid: 7486399
doi: 10.1038/s41467-020-18319-6
Chen R, Wang K, Yu J, Howard D, French L, Chen Z, et al. The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Front Neurol. 2020;11:573095.
pubmed: 33551947
doi: 10.3389/fneur.2020.573095
Torices S, Cabrera R, Stangis M, Naranjo O, Fattakhov N, Teglas T, 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.
pubmed: 34325716
pmcid: 8319595
doi: 10.1186/s12974-021-02210-2
Cui H, Su S, Cao Y, Ma C, Qiu W. The altered anatomical distribution of ACE2 in the brain with Alzheimer’s disease pathology. Front Cell Dev Biol. 2021;9:684874.
pubmed: 34249938
pmcid: 8267059
doi: 10.3389/fcell.2021.684874
Ding Q, Shults NV, Gychka SG, Harris BT, Suzuki YJ. Protein expression of angiotensin-converting enzyme 2 (ACE2) is upregulated in brains with Alzheimer’s disease. Int J Mol Sci. 2021;22:1687.
pubmed: 33567524
pmcid: 7914443
doi: 10.3390/ijms22041687
Schimmel L, Chew KY, Stocks CJ, Yordanov TE, Essebier P, Kulasinghe A, et al. Endothelial cells are not productively infected by SARS-CoV-2. Clin Transl Immunol. 2021;10:e1350.
doi: 10.1002/cti2.1350
D’Onofrio N, Scisciola L, Sardu C, Trotta MC, De Feo M, Maiello C, et al. Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte. Cardiovasc Diabetol. 2021;20:99.
pubmed: 33962629
pmcid: 8104461
doi: 10.1186/s12933-021-01286-7
Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X, et al. A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell. 2020;27:125–36. e127.
pubmed: 32579880
pmcid: 7303620
doi: 10.1016/j.stem.2020.06.015
Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.
pubmed: 25686105
pmcid: 4392179
doi: 10.1038/nm.3806
Wang L, Xiang Y. Spike glycoprotein-mediated entry of SARS coronaviruses. Viruses. 2020;12:1289.
pubmed: 33187074
pmcid: 7696831
doi: 10.3390/v12111289
Chen Y, Zhang YN, Yan R, Wang G, Zhang Y, Zhang ZR, et al. ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker. Signal Transduct Target Ther. 2021;6:315.
pubmed: 34433803
pmcid: 8385704
doi: 10.1038/s41392-021-00740-y
Ferreira AC, Soares VC, de Azevedo-Quintanilha IG, Dias S, Fintelman-Rodrigues N, Sacramento CQ, et al. SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes. Cell Death Disco. 2021;7:43.
doi: 10.1038/s41420-021-00428-w
Theobald SJ, Simonis A, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, et al. Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med. 2021;13:e14150.
pubmed: 34133077
pmcid: 8350892
doi: 10.15252/emmm.202114150
Junqueira C, Crespo A, Ranjbar S, de Lacerda LB, Lewandrowski M, Ingber J, et al. FcgammaR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature. 2022;606:576–84.
pubmed: 35385861
pmcid: 10071495
doi: 10.1038/s41586-022-04702-4
Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H, Zhao J, et al. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature. 2022;606:585–93.
pubmed: 35483404
pmcid: 9288243
doi: 10.1038/s41586-022-04802-1
Matschke J, Lahann H, Krasemann S, Altmeppen H, Pfefferle S, Galliciotti G, et al. Young COVID-19 Patients Show a Higher Degree of Microglial Activation When Compared to Controls. Front Neurol. 2022;13:908081.
pubmed: 35785352
pmcid: 9243237
doi: 10.3389/fneur.2022.908081
Cama VF, Marin-Prida J, Acosta-Rivero N, Acosta EF, Diaz LO, Casadesus AV, et al. The microglial NLRP3 inflammasome is involved in human SARS-CoV-2 cerebral pathogenicity: A report of three post-mortem cases. J Neuroimmunol. 2021;361:577728.
pubmed: 34619427
pmcid: 8480138
doi: 10.1016/j.jneuroim.2021.577728
Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O, van Riel D. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci. 2022;45:358–68.
pubmed: 35279295
pmcid: 8890977
doi: 10.1016/j.tins.2022.02.006
Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021;218.
Crunfli F, Carregari VC, Veras FP, Silva LS, Nogueira MH, Antunes A, et al. Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc Natl Acad Sci USA. 2022;119:e2200960119.
pubmed: 35951647
pmcid: 9436354
doi: 10.1073/pnas.2200960119
Zhang L, Zhou L, Bao L, Liu J, Zhu H, Lv Q, et al. SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct Target Ther. 2021;6:337.
pubmed: 34489403
pmcid: 8419672
doi: 10.1038/s41392-021-00719-9
Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D, Carter AP, et al. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell. 2020;27:951–61.
pubmed: 33113348
pmcid: 7553118
doi: 10.1016/j.stem.2020.10.001
Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022;17:307–20.
doi: 10.1016/j.stemcr.2021.12.011
Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24:168–75.
pubmed: 33257876
doi: 10.1038/s41593-020-00758-5
Bulfamante G, Bocci T, Falleni M, Campiglio L, Coppola S, Tosi D, et al. Brainstem neuropathology in two cases of COVID-19: SARS-CoV-2 trafficking between brain and lung. J Neurol. 2021;268:4486–91.
pubmed: 34003372
pmcid: 8129960
doi: 10.1007/s00415-021-10604-8
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.
pubmed: 34611326
doi: 10.1038/s41580-021-00418-x
Hikmet F, Mear L, Edvinsson A, Micke P, Uhlen M, Lindskog C. The protein expression profile of ACE2 in human tissues. Mol Syst Biol. 2020;16:e9610.
pubmed: 32715618
pmcid: 7383091
doi: 10.15252/msb.20209610
Lindskog C, Mear L, Virhammar J, Fallmar D, Kumlien E, Hesselager G, et al. Protein expression profile of ACE2 in the normal and COVID-19-affected human brain. J Proteome Res. 2022;21:2137–45.
pubmed: 35901083
pmcid: 9364976
doi: 10.1021/acs.jproteome.2c00184
Labandeira CM, Pedrosa MA, Quijano A, Valenzuela R, Garrido-Gil P, Sanchez-Andrade M, et al. Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson s disease. NPJ Parkinsons Dis. 2022;8:76.
pubmed: 35701430
pmcid: 9198025
doi: 10.1038/s41531-022-00340-9
Arthur JM, Forrest JC, Boehme KW, Kennedy JL, Owens S, Herzog C, et al. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLoS One. 2021;16:e0257016.
pubmed: 34478478
pmcid: 8415618
doi: 10.1371/journal.pone.0257016
Jiang Y, Duffy F, Hadlock J, Raappana A, Styrchak S, Beck I, et al. Angiotensin II receptor I auto-antibodies following SARS-CoV-2 infection. PLoS One. 2021;16:e0259902.
pubmed: 34788328
pmcid: 8598062
doi: 10.1371/journal.pone.0259902
Niles MA, Gogesch P, Kronhart S, Ortega Iannazzo S, Kochs G, Waibler Z, et al. Macrophages and dendritic cells are not the major source of pro-inflammatory cytokines upon SARS-CoV-2 infection. Front Immunol. 2021;12:647824.
pubmed: 34122407
pmcid: 8187925
doi: 10.3389/fimmu.2021.647824
Ratajczak MZ, Bujko K, Ciechanowicz A, Sielatycka K, Cymer M, Marlicz W, et al. SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45(-) precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 inflammasome. Stem Cell Rev Rep. 2021;17:266–77.
pubmed: 32691370
doi: 10.1007/s12015-020-10010-z
Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol. 2019;10:50.
pubmed: 30761102
pmcid: 6361828
doi: 10.3389/fmicb.2019.00050
Nieto-Torres JL, Verdia-Baguena C, Jimenez-Guardeno JM, Regla-Nava JA, Castano-Rodriguez C, Fernandez-Delgado R, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology. 2015;485:330–9.
pubmed: 26331680
doi: 10.1016/j.virol.2015.08.010
Siu KL, Yuen KS, Castano-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J. 2019;33:8865–77.
pubmed: 31034780
pmcid: 6662968
doi: 10.1096/fj.201802418R
Pan P, Shen M, Yu Z, Ge W, Chen K, Tian M, et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat Commun. 2021;12:4664.
pubmed: 34341353
pmcid: 8329225
doi: 10.1038/s41467-021-25015-6
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.
pubmed: 19570822
doi: 10.4049/jimmunol.0901363
Dosch SF, Mahajan SD, Collins AR. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro. Virus Res. 2009;142:19–27.
pubmed: 19185596
doi: 10.1016/j.virusres.2009.01.005
Khan S, Shafiei MS, Longoria C, Schoggins JW, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-kappaB pathway. Elife. 2021;10:e68563.
pubmed: 34866574
pmcid: 8709575
doi: 10.7554/eLife.68563
Fares MB, Jagannath S, Lashuel HA. Reverse engineering Lewy bodies: how far have we come and how far can we go? Nat Rev Neurosci. 2021;22:111–31.
pubmed: 33432241
doi: 10.1038/s41583-020-00416-6
Filatov A, Sharma P, Hindi F, Espinosa PS. Neurological complications of coronavirus disease (COVID-19): encephalopathy. Cureus. 2020;12:e7352.
pubmed: 32328364
pmcid: 7170017
Espinosa PS, Rizvi Z, Sharma P, Hindi F, Filatov A. Neurological complications of coronavirus disease (COVID-19): encephalopathy, MRI brain and cerebrospinal fluid findings: case 2. Cureus. 2020;12:e7930.
pubmed: 32499974
pmcid: 7266087
Limphaibool N, Iwanowski P, Holstad MJV, Kobylarek D, Kozubski W. Infectious etiologies of Parkinsonism: pathomechanisms and clinical implications. Front Neurol. 2019;10:652.
pubmed: 31275235
pmcid: 6593078
doi: 10.3389/fneur.2019.00652
Ramos HJ, Lanteri MC, Blahnik G, Negash A, Suthar MS, Brassil MM, et al. IL-1beta signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog. 2012;8:e1003039.
pubmed: 23209411
pmcid: 3510243
doi: 10.1371/journal.ppat.1003039
Beatman EL, Massey A, Shives KD, Burrack KS, Chamanian M, Morrison TE, et al. Alpha-synuclein expression restricts RNA viral infections in the brain. J Virol. 2015;90:2767–82.
pubmed: 26719256
doi: 10.1128/JVI.02949-15
Tulisiak CT, Mercado G, Peelaerts W, Brundin L, Brundin P. Can infections trigger alpha-synucleinopathies? Prog Mol Biol Transl Sci. 2019;168:299–322.
pubmed: 31699323
pmcid: 6857718
doi: 10.1016/bs.pmbts.2019.06.002
Blanco-Palmero VA, Azcarate-Diaz FJ, Ruiz-Ortiz M, Laespada-Garcia MI, Rabano-Suarez P, Mendez-Guerrero A, et al. Serum and CSF alpha-synuclein levels do not change in COVID-19 patients with neurological symptoms. J Neurol. 2021;268:3116–24.
pubmed: 33606070
pmcid: 7892700
doi: 10.1007/s00415-021-10444-6
Erickson MA, Rhea EM, Knopp RC, Banks WA. Interactions of SARS-CoV-2 with the Blood-Brain Barrier. Int J Mol Sci. 2021;22:2681.
pubmed: 33800954
pmcid: 7961671
doi: 10.3390/ijms22052681
Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22.
pubmed: 32240762
pmcid: 7146689
doi: 10.1016/j.bbi.2020.03.031
Poloni TE, Medici V, Moretti M, Visona SD, Cirrincione A, Carlos AF, et al. COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Brain Pathol. 2021;31:e12997.
pubmed: 34145669
pmcid: 8412067
doi: 10.1111/bpa.12997
Maes M, Tedesco Junior WLD, Lozovoy MAB, Mori MTE, Danelli T, Almeida ERD, et al. In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach. Mol Psychiatry. 2022;27:1945–55.
pubmed: 35022530
pmcid: 8752583
doi: 10.1038/s41380-021-01431-4
Kumari P, Rothan HA, Natekar JP, Stone S, Pathak H, Strate PG, et al. Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses. 2021;13:132.
pubmed: 33477869
pmcid: 7832889
doi: 10.3390/v13010132
Dinnon KH 3rd, Leist SR, Schafer A, Edwards CE, Martinez DR, Montgomery SA, et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature. 2020;586:560–6.
pubmed: 32854108
pmcid: 8034761
doi: 10.1038/s41586-020-2708-8
Schwabenland M, Salie H, Tanevski J, Killmer S, Lago MS, Schlaak AE, et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity. 2021;54:1594–610.
pubmed: 34174183
pmcid: 8188302
doi: 10.1016/j.immuni.2021.06.002
Brown EG, Chahine LM, Goldman SM, Korell M, Mann E, Kinel DR, et al. The effect of the COVID-19 pandemic on people with Parkinson’s disease. J Parkinsons Dis. 2020;10:1365–77.
pubmed: 32925107
pmcid: 7683050
doi: 10.3233/JPD-202249
Cilia R, Bonvegna S, Straccia G, Andreasi NG, Elia AE, Romito LM, et al. Effects of COVID-19 on Parkinson’s disease clinical features: a community-based case-control study. Mov Disord. 2020;35:1287–92.
pubmed: 32449528
pmcid: 7280741
doi: 10.1002/mds.28170
Philippens I, Boszormenyi KP, Wubben JAM, Fagrouch ZC, van Driel N, Mayenburg AQ, et al. Brain inflammation and intracellular alpha-synuclein aggregates in macaques after SARS-CoV-2 infection. Viruses. 2022;14:776.
pubmed: 35458506
pmcid: 9025893
doi: 10.3390/v14040776
Zeng J, Xie X, Feng XL, Xu L, Han JB, Yu D, et al. Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice. EBioMedicine. 2022;75:103803.
pubmed: 34979342
doi: 10.1016/j.ebiom.2021.103803
Mullard A. NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Disco. 2019;18:405–7.
doi: 10.1038/d41573-019-00086-9