Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent responsible for coronavirus disease (COVID-19), is an issue of global concern since March 2020. The respiratory manifestations of COVID-19 have widely been explained in the last couple of months of the pandemic. Initially, the virus was thought to be restricted to the pulmonary system; however, as time progressed and cases increased during the second wave of COVID-19, the virus affected other organs, including the nervous system. The neurological implication of SARS-CoV-2 infection is mounting, as substantiated by various reports, and in the majority of COVID-19 patients with neurological symptoms, the penetration of SARS-CoV-2 in the central nervous system (CNS) is likely. SARS-CoV-2 can enter the nervous system by exploiting the routes of olfactory mucosa, olfactory and sensory nerve endings, or endothelial and nerve tissues, thus crossing the neural-mucosal interface in the olfactory mucosa in the nose. Owing to multifactorial and complex pathogenic mechanisms, COVID-19 adds a large-scale risk to the entire nervous system. A thorough understanding of SARSCoV- 2 neurological damage is still vague; however, our comprehension of the virus is rapidly developing. The present comprehensive review will gain insights and provide neurological dimensions of COVID-19 and their associated anomalies. The review presents the entry routes of SARS-CoV-2 into the CNS to ascertain potential targets in the tissues owing to infection. We also discuss the molecular mechanisms involved, the array of clinical symptoms, and various nervous system diseases following the attack of SARS-CoV-2.
Keywords: ACE2, BBB, CNS, COVID-19, SARS-CoV-2, respiratory manifestations.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[http://dx.doi.org/10.1016/j.jns.2020.116824] [PMID: 32299010]
[http://dx.doi.org/10.1016/j.ijid.2020.03.062] [PMID: 32251791]
[http://dx.doi.org/10.1001/jamaneurol.2020.1127] [PMID: 32275288]
[http://dx.doi.org/10.1038/s41593-020-00758-5] [PMID: 33257876]
[http://dx.doi.org/10.1053/j.semdp.2019.04.006] [PMID: 31054790]
[http://dx.doi.org/10.1016/j.idc.2019.07.001] [PMID: 31668196]
[http://dx.doi.org/10.3390/v12010014] [PMID: 31861926]
[http://dx.doi.org/10.3201/eid1002.030638] [PMID: 15030709]
[http://dx.doi.org/10.1002/jmv.25728] [PMID: 32104915]
[http://dx.doi.org/10.1136/svn-2020-000431] [PMID: 32616524]
[http://dx.doi.org/10.5812/ircmj.102828]
[http://dx.doi.org/10.1016/S1474-4422(20)30109-5] [PMID: 32246917]
[http://dx.doi.org/10.1101/2020.03.16.20035105]
[http://dx.doi.org/10.1148/radiol.2020201187] [PMID: 32228363]
[http://dx.doi.org/10.1016/j.jocn.2020.04.062] [PMID: 32312628]
[http://dx.doi.org/10.1056/NEJMc2019373] [PMID: 32530583]
[http://dx.doi.org/10.1002/path.4461] [PMID: 25294743]
[http://dx.doi.org/10.1038/s41586-020-2008-3] [PMID: 32015508]
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[http://dx.doi.org/10.1038/s41564-020-0695-z] [PMID: 32123347]
[http://dx.doi.org/10.1093/nsr/nwaa036] [PMID: 34676127]
[http://dx.doi.org/10.1038/s41467-021-22785-x] [PMID: 34168138]
[http://dx.doi.org/10.1038/s41591-020-0820-9] [PMID: 32284615]
[http://dx.doi.org/10.2174/2666796702666210202125638]
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[http://dx.doi.org/10.1128/JVI.00737-08] [PMID: 18495771]
[http://dx.doi.org/10.1152/ajpregu.00292.2006] [PMID: 16946085]
[http://dx.doi.org/10.7554/eLife.59136] [PMID: 32729463]
[http://dx.doi.org/10.1126/sciadv.abc5801] [PMID: 32937591]
[http://dx.doi.org/10.1007/s11427-020-1661-4] [PMID: 32146694]
[http://dx.doi.org/10.1164/rccm.2020C1] [PMID: 32223716]
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[http://dx.doi.org/10.1001/jama.2020.4269] [PMID: 32196079]
[http://dx.doi.org/10.1016/j.micinf.2020.01.004] [PMID: 32032682]
[http://dx.doi.org/10.3201/eid2607.200282] [PMID: 32255761]
[http://dx.doi.org/10.1146/annurev-virology-110615-042301] [PMID: 27578435]
[http://dx.doi.org/10.1002/rmv.2122] [PMID: 32602627]
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[http://dx.doi.org/10.1073/pnas.0505577102] [PMID: 16081529]
[http://dx.doi.org/10.1002/path.1570] [PMID: 15141377]
[http://dx.doi.org/10.1101/2020.05.11.088500]
[http://dx.doi.org/10.1007/s11906-010-0105-7] [PMID: 20424953]
[http://dx.doi.org/10.1111/jnc.13641] [PMID: 27085714]
[http://dx.doi.org/10.1016/j.brainresrev.2007.06.002] [PMID: 17659349]
[http://dx.doi.org/10.1093/infdis/jiv499] [PMID: 26486634]
[http://dx.doi.org/10.3389/fncel.2020.592214] [PMID: 33304243]
[http://dx.doi.org/10.1016/j.coviro.2014.12.009] [PMID: 25681709]
[http://dx.doi.org/10.1016/j.virusres.2014.09.011] [PMID: 25281913]
[http://dx.doi.org/10.1016/j.virusres.2011.12.021] [PMID: 22248641]
[http://dx.doi.org/10.2741/3595] [PMID: 19482613]
[http://dx.doi.org/10.4049/jimmunol.173.6.4030] [PMID: 15356152]
[http://dx.doi.org/10.1021/acs.jproteome.5b00883] [PMID: 27142340]
[http://dx.doi.org/10.1016/j.virusres.2007.01.022] [PMID: 17825937]
[http://dx.doi.org/10.1038/nrmicro1343] [PMID: 16415928]
[http://dx.doi.org/10.1001/jama.2020.3786]
[http://dx.doi.org/10.1136/bmj.m1443] [PMID: 32317267]
[http://dx.doi.org/10.1124/pr.117.014647] [PMID: 29496890]
[http://dx.doi.org/10.1128/mBio.01476-14] [PMID: 25161189]
[http://dx.doi.org/10.1186/s40478-020-01024-2] [PMID: 32847628]
[http://dx.doi.org/10.1128/9781555815790.ch20]
[http://dx.doi.org/10.1128/CMR.00118-13] [PMID: 25278572]
[http://dx.doi.org/10.1017/neu.2016.47] [PMID: 27692004]
[http://dx.doi.org/10.1152/ajpregu.00268.2005] [PMID: 16357100]
[http://dx.doi.org/10.1186/s12974-018-1192-7] [PMID: 29764485]
[http://dx.doi.org/10.1021/acschemneuro.0c00122] [PMID: 32167747]
[http://dx.doi.org/10.1016/j.neuron.2020.06.032] [PMID: 32640192]
[http://dx.doi.org/10.1212/WNL.0000000000010111] [PMID: 32546655]
[http://dx.doi.org/10.1002/ana.25856] [PMID: 32737995]
[http://dx.doi.org/10.1001/jamaneurol.2020.2125] [PMID: 32469400]
[http://dx.doi.org/10.1128/JVI.00404-18] [PMID: 29925652]
[http://dx.doi.org/10.1002/oby.22809] [PMID: 32237199]
[http://dx.doi.org/10.1093/cid/ciaa330] [PMID: 32215618]
[http://dx.doi.org/10.1007/s00405-020-05965-1] [PMID: 32253535]
[http://dx.doi.org/10.1007/s11940-020-00647-z] [PMID: 32994698]
[http://dx.doi.org/10.3390/ijms21155475] [PMID: 32751841]
[http://dx.doi.org/10.1016/j.cell.2020.08.028]
[http://dx.doi.org/10.1007/978-81-322-1777-0_6] [PMID: 24619619]
[http://dx.doi.org/10.1001/jamaneurol.2020.2065] [PMID: 32469387]
[http://dx.doi.org/10.1189/jlb.0503207] [PMID: 12960230]
[http://dx.doi.org/10.1002/jmv.26521] [PMID: 32964419]
[http://dx.doi.org/10.1002/jmv.25915] [PMID: 32314810]
[http://dx.doi.org/10.1128/JVI.01702-06] [PMID: 17108019]
[http://dx.doi.org/10.1016/j.bbi.2019.09.016] [PMID: 31550500]
[http://dx.doi.org/10.1038/s41577-020-0402-6] [PMID: 32728222]
[http://dx.doi.org/10.1056/NEJMra052211] [PMID: 16192482]
[http://dx.doi.org/10.1038/nature21029] [PMID: 28099414]
[http://dx.doi.org/10.1038/nature18283] [PMID: 27337340]
[http://dx.doi.org/10.1186/s13054-020-03364-w] [PMID: 33302991]
[http://dx.doi.org/10.1038/s41591-021-01499-z] [PMID: 34480127]
[http://dx.doi.org/10.1080/19420862.2018.1415671] [PMID: 29300693]
[http://dx.doi.org/10.1089/jir.2016.0017] [PMID: 27336613]
[http://dx.doi.org/10.1186/s13054-020-03158-0] [PMID: 32680535]
[http://dx.doi.org/10.1038/s41375-021-01299-x] [PMID: 34031531]
[http://dx.doi.org/10.1101/cshperspect.a016295] [PMID: 25190079]
[http://dx.doi.org/10.1097/01.shk.0000191336.01036.fe] [PMID: 16374376]
[http://dx.doi.org/10.1097/ALN.0000000000001083] [PMID: 26982508]
[http://dx.doi.org/10.1038/nn.4477] [PMID: 28092663]
[http://dx.doi.org/10.3906/sag-2004-168] [PMID: 32299202]
[http://dx.doi.org/10.1016/j.bbi.2005.03.015] [PMID: 15922555]
[http://dx.doi.org/10.1038/nature01321] [PMID: 12490958]
[http://dx.doi.org/10.1021/acschemneuro.0c00201] [PMID: 32320211]
[http://dx.doi.org/10.1056/NEJMra0808281] [PMID: 21190458]
[http://dx.doi.org/10.1213/ANE.0000000000003668] [PMID: 30252709]
[http://dx.doi.org/10.1007/BF03402177] [PMID: 14571320]
[http://dx.doi.org/10.3389/fneur.2020.573718] [PMID: 33324324]
[http://dx.doi.org/10.1089/sur.2012.126] [PMID: 22913335]
[http://dx.doi.org/10.1016/j.toxrep.2020.04.012] [PMID: 32355638]
[http://dx.doi.org/10.1371/journal.pone.0249128] [PMID: 33760875]
[http://dx.doi.org/10.1056/NEJMc2008597] [PMID: 32294339]
[http://dx.doi.org/10.1093/cid/cit458] [PMID: 23861361]
[http://dx.doi.org/10.1007/s13760-020-01401-7] [PMID: 32524537]
[http://dx.doi.org/10.1038/s41582-020-0398-3] [PMID: 32839585]
[http://dx.doi.org/10.1016/j.bbih.2020.100094] [PMID: 33521692]
[http://dx.doi.org/10.3174/ajnr.A6715] [PMID: 32816764]
[http://dx.doi.org/10.1111/ene.14444] [PMID: 32681611]
[http://dx.doi.org/10.1093/brain/awaa240] [PMID: 32637987]
[http://dx.doi.org/10.12659/AJCR.925641] [PMID: 32799213]
[http://dx.doi.org/10.1186/s41983-020-00244-6] [PMID: 33250631]
[http://dx.doi.org/10.1016/j.bbi.2020.05.022] [PMID: 32389697]
[http://dx.doi.org/10.1093/brain/awaa337] [PMID: 33064794]
[http://dx.doi.org/10.3389/fneur.2020.00805] [PMID: 32754113]
[http://dx.doi.org/10.1111/ene.14913] [PMID: 33982853]
[http://dx.doi.org/10.1097/QCO.0000000000000355] [PMID: 28118219]
[http://dx.doi.org/10.1016/j.jns.2019.01.050] [PMID: 30731305]
[http://dx.doi.org/10.1136/archdischild-2014-306813] [PMID: 25256088]
[http://dx.doi.org/10.1097/INF.0000000000002313] [PMID: 31205243]
[http://dx.doi.org/10.1136/bmj.39409.673657.AE] [PMID: 18174598]
[http://dx.doi.org/10.1542/peds.105.2.316] [PMID: 10654948]
[http://dx.doi.org/10.1212/WNL.0000000000003509] [PMID: 27986877]
[http://dx.doi.org/10.1001/jama.2020.2648] [PMID: 32091533]
[http://dx.doi.org/10.1136/bmj.m1198] [PMID: 32217618]
[http://dx.doi.org/10.1002/jmv.25740] [PMID: 32115733]
[http://dx.doi.org/10.1111/ene.14462] [PMID: 32757404]
[http://dx.doi.org/10.1136/jnnp-2020-324837] [PMID: 33158914]
[http://dx.doi.org/10.1111/jns.12419] [PMID: 33112450]
[http://dx.doi.org/10.1093/brain/awab279]
[http://dx.doi.org/10.1002/ana.410270706] [PMID: 2194420]
[http://dx.doi.org/10.1378/chest.121.4.1262] [PMID: 11948062]
[http://dx.doi.org/10.1056/NEJMoa1605564] [PMID: 27705091]
[http://dx.doi.org/10.1056/NEJMc2009191] [PMID: 32302082]
[http://dx.doi.org/10.1212/WNL.59.4.499] [PMID: 12236201]
[http://dx.doi.org/10.1016/j.ncl.2012.09.008] [PMID: 23186897]
[http://dx.doi.org/10.1016/j.autrev.2011.05.018] [PMID: 21621005]
[http://dx.doi.org/10.1038/nrneurol.2016.21] [PMID: 26943779]
[http://dx.doi.org/10.1016/j.clineuro.2020.106451] [PMID: 33388661]
[http://dx.doi.org/10.1001/jamaneurol.2020.2581] [PMID: 32589189]
[http://dx.doi.org/10.1212/WNL.0000000000000560] [PMID: 24871874]
[http://dx.doi.org/10.1212/NXI.0000000000000835] [PMID: 32646885]
[http://dx.doi.org/10.1212/WNL.0000000000009507] [PMID: 32241953]
[http://dx.doi.org/10.1016/j.msard.2020.102452] [PMID: 32823148]
[http://dx.doi.org/10.1097/WNF.0b013e318204cd90] [PMID: 21242742]
[http://dx.doi.org/10.1177/1756285614563522] [PMID: 25584072]
[http://dx.doi.org/10.1111/j.1365-2567.2009.03115.x] [PMID: 19740383]
[http://dx.doi.org/10.1177/1756286418773025] [PMID: 29774057]
[PMID: 18609733]
[http://dx.doi.org/10.1007/s00415-020-10362-z] [PMID: 33416999]
[http://dx.doi.org/10.4161/mabs.22771] [PMID: 23211638]
[http://dx.doi.org/10.1097/WNF.0b013e3181cbf825] [PMID: 20061941]
[http://dx.doi.org/10.3390/cells8010024] [PMID: 30621015]
[http://dx.doi.org/10.3390/neurolint12030016] [PMID: 33287177]
[http://dx.doi.org/10.3233/HAB-1997-8102] [PMID: 9265500]
[http://dx.doi.org/10.2147/tcrm.2007.3.2.259] [PMID: 18360634]
[http://dx.doi.org/10.1093/brain/awq386] [PMID: 21354971]
[http://dx.doi.org/10.1007/s40265-014-0212-x] [PMID: 24740824]
[http://dx.doi.org/10.1016/S0074-7742(07)79024-4] [PMID: 17531858]
[http://dx.doi.org/10.2165/11591110-000000000-00000] [PMID: 21649449]