open access
Neuro-COVID-19: an insidious virus in action
Affiliations- Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
open access
Abstract
Introduction: The punishing effect of the pandemic outbreak of the disease termed COVID-19 (coronavirus disease-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) impelled the author to gather the facts about the nature of this new pathogen. The aim of this paper was to discuss the mechanisms involved in the pathogenesis of neurological complications during the course of COVID-19.
State of the art: Neurological symptoms, such as impairment of taste or smell, headache, nausea and/or altered consciousness, are commonly described in COVID-19 patients, although there are emerging clinical reports of more serious conditions such as acute cerebrovascular accidents, encephalitis and demyelinating disease. Whether these manifestations are the direct consequence of viral invasion of the central nervous system, or are caused by indirect mechanisms, is yet to be established. Studies to date have indicated that neurological lesions found in the brains of COVID-19 patients are a combination of direct cytopathic effects caused by SARS-CoV-2 replication and indirect effects due to hypoxia, excessive cytokine reaction, impaired
immune response, and cerebrovascular injury induced by viral infection. Studies are still pending into possible routes of SARS-CoV-2 neuroinvasion encompassing the haematopoietic pathway via the blood-brain barrier and retrograde axonal transport through the cranial nerves.
Clinical implications: A thorough understanding of SARS-CoV-2 involvement in neurological complications is still lacking. However, our knowledge about SARS-CoV-2 virulence is rapidly expanding, and that has inclined the author to prepare this comprehensive review in the hope that it will improve understanding about the molecular mechanisms underlying neurological abnormalities associated with COVID-19.
Future directions: A future detailed study should explore the diagnostics and disease mechanisms so as to enable the development of better therapeutic strategies to reduce the severity of COVID-19 neurological complications.
Abstract
Introduction: The punishing effect of the pandemic outbreak of the disease termed COVID-19 (coronavirus disease-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) impelled the author to gather the facts about the nature of this new pathogen. The aim of this paper was to discuss the mechanisms involved in the pathogenesis of neurological complications during the course of COVID-19.
State of the art: Neurological symptoms, such as impairment of taste or smell, headache, nausea and/or altered consciousness, are commonly described in COVID-19 patients, although there are emerging clinical reports of more serious conditions such as acute cerebrovascular accidents, encephalitis and demyelinating disease. Whether these manifestations are the direct consequence of viral invasion of the central nervous system, or are caused by indirect mechanisms, is yet to be established. Studies to date have indicated that neurological lesions found in the brains of COVID-19 patients are a combination of direct cytopathic effects caused by SARS-CoV-2 replication and indirect effects due to hypoxia, excessive cytokine reaction, impaired
immune response, and cerebrovascular injury induced by viral infection. Studies are still pending into possible routes of SARS-CoV-2 neuroinvasion encompassing the haematopoietic pathway via the blood-brain barrier and retrograde axonal transport through the cranial nerves.
Clinical implications: A thorough understanding of SARS-CoV-2 involvement in neurological complications is still lacking. However, our knowledge about SARS-CoV-2 virulence is rapidly expanding, and that has inclined the author to prepare this comprehensive review in the hope that it will improve understanding about the molecular mechanisms underlying neurological abnormalities associated with COVID-19.
Future directions: A future detailed study should explore the diagnostics and disease mechanisms so as to enable the development of better therapeutic strategies to reduce the severity of COVID-19 neurological complications.
Keywords
coronavirus, COVID-19, SARS-CoV-2, CNS complications
About this articleTitle
Neuro-COVID-19: an insidious virus in action
Journal
Neurologia i Neurochirurgia Polska
Issue
Article type
Review Article
Pages
48-60
Published online
2021-10-13
Page views
6842
Article views/downloads
1685
DOI
Pubmed
Bibliographic record
Neurol Neurochir Pol 2022;56(1):48-60.
Keywords
coronavirus
COVID-19
SARS-CoV-2
CNS complications
Authors
Jolanta Bratosiewicz-Wąsik
References (110)- Hui DS, I Azhar E, Madani TA, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020; 91: 264–266.
- Coronavirus disease (COVID-19) pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.
- WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. https://covid19.who.int/.
- Wahba L, Jain N, Fire AZ, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798): 270–273.
- Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020; 395(10223): 507–513.
- Wang D, Hu Bo, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323(11): 1061–1069.
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020; 395(10223): 497–506.
- Moein ST, Hashemian SM, Mansourafshar B, et al. Smell dysfunction: a biomarker for COVID-19. Int Forum Allergy Rhinol. 2020; 10(8): 944–950.
- Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med. 2020; 26(4): 506–510.
- Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine. 2020; 8(5): 475–481.
- International Committee on Taxonomy of Viruses. https://talk.ictvonline.org/.
- Bratosiewicz-Wąsik J, Wąsik TJ. Does virus-receptor interplay influence human coronaviruses infection outcome? Med Sci Monit. 2020; 26: e928572.
- Naqvi AA, Fatima K, Mohammad T, et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim Biophys Acta Mol Basis Dis. 2020; 1866(10): 165878.
- Zhang YZ, Holmes EC. A genomic perspective on the origin and emergence of SARS-CoV-2. Cell. 2020; 181(2): 223–227.
- McBride R, van Zyl M, Fielding BC. The coronavirus nucleocapsid is a multifunctional protein. Viruses. 2014; 6(8): 2991–3018.
- Hoffmann M, Kleine-Weber H, Schroeder S, et al. 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.
- Padmanabhan P, Desikan R, Dixit NM. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS Comput Biol. 2020; 16(12): e1008461.
- Chen Yu, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020; 92(10): 2249.
- Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015; 1282: 1–23.
- Walls AC, Park YJ, Tortorici MA, et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 181(2): 281–292.e6.
- Fuentes-Prior P. Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection. J Biol Chem. 2021; 296: 100135.
- Tang T, Jaimes JA, Bidon MK, et al. Proteolytic activation of SARS-CoV-2 spike at the S1/S2 boundary: potential role of proteases beyond furin. ACS Infect Dis. 2021; 7(2): 264–272.
- Heald-Sargent T, Gallagher T. Ready, set, fuse! The coronavirus spike protein and acquisition of fusion competence. Viruses. 2012; 4(4): 557–580.
- Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020; 370(6518): 856–860.
- Davies J, Randeva HS, Chatha K, et al. Neuropilin‑1 as a new potential SARS‑CoV‑2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID‑19. Mol Med Rep. 2020; 22(5): 4221–4226.
- Wang Ke, Chen W, Zhang Z, et al. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduct Target Ther. 2020; 5(1): 283.
- Qiao J, Li W, Bao J, et al. 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. 2020; 533(4): 867–871.
- Wnuk M, Sawczyńska K, Kęsek T, et al. Neurological symptoms in hospitalised patients with COVID-19 and their association with in-hospital mortality. Neurol Neurochir Pol. 2021; 55(3): 314–321.
- Xiong W, Mu J, Guo J, et al. New onset neurologic events in people with COVID-19 in 3 regions in China. Neurology. 2020; 95(11): e1479–e1487.
- Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020; 77(6): 683–690.
- Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020; 382(23): 2268–2270.
- Kandemirli SG, Dogan L, Sarikaya ZT, et al. Brain MRI findings in patients in the Intensive Care Unit with COVID-19 infection. Radiology. 2020; 297(1): E232–E235.
- Keyhanian K, Umeton RP, Mohit B, et al. SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation. J Neuroimmunol. 2020 [Epub ahead of print]; 350: 577436.
- Wnuk M, Sawczyńska K, Kęsek T, et al. Neurological symptoms in hospitalised patients with COVID-19 and their association with in-hospital mortality. Neurol Neurochir Pol. 2021; 55(3): 314–321.
- Stachura T, Celejewska-Wójcik N, Polok K, et al. A clinical profile and factors associated with severity of the disease among Polish patients hospitalized due to COVID-19 - an observational study. Adv Respir Med. 2021; 89(2): 124–134.
- Mania A, Mazur-Melewska K, Lubarski K, et al. Wide spectrum of clinical picture of COVID-19 in children - From mild to severe disease. J Infect Public Health. 2021; 14(3): 374–379.
- Przytuła F, Błądek S, Sławek J. Two COVID-19-related video-accompanied cases of severe ataxia-myoclonus syndrome. Neurol Neurochir Pol. 2021; 55(3): 310–313.
- Krajewski PK, Maj J, Szepietowski JC. Cutaneous hyperaesthesia in SARS-CoV-2 infection: rare but not unique clinical manifestation. Acta Derm Venereol. 2021; 101(1): adv00366.
- Fodoulian L, Tuberosa J, Rossier D, et al. SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain. iScience. 2020; 23(12): 101839.
- Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020; 11(7): 995–998.
- Ding Y, He Li, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004; 203(2): 622–630.
- Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020; 94: 55–58.
- Liu JM, Tan BH, Wu S, et al. Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS-CoV-2 infection. J Med Virol. 2021; 93(3): 1304–1313.
- Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020; 92(7): 699–702.
- Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020; 383(6): 590–592.
- Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of Covid-19. N Engl J Med. 2020; 383(10): 989–992.
- Tiwari SK, Wang S, Smith D, et al. Revealing tissue-specific SARS-CoV-2 infection and host responses using human stem cell-derived lung and cerebral organoids. Stem Cell Reports. 2021; 16(3): 437–445.
- Varga Z, Flammer A, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. The Lancet. 2020; 395(10234): 1417–1418.
- Song E, Zhang Ce, Israelow B, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021; 218(3).
- Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis. 2020; 146: 105131.
- Chu H, Chan JW, Yuen TT, et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. The Lancet Microbe. 2020; 1(1): e14–e23.
- Ramani A, Müller L, Ostermann PN, et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020; 39(20): e106230.
- Rathnasinghe R, Strohmeier S, Amanat F, et al. Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection. Emerg Microbes Infect. 2020; 9(1): 2433–2445.
- Zheng J, Wong LYR, Li K, et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature. 2021; 589(7843): 603–607.
- Yinda CK, Port JR, Bushmaker T, et al. K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathog. 2021; 17(1): e1009195.
- Zou X, Chen Ke, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020; 14(2): 185–192.
- Chen R, Wang K, Yu J, 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.
- Lukiw WJ, Pogue A, Hill JM. SARS-CoV-2 infectivity and neurological targets in the brain. Cell Mol Neurobiol. 2020 [Epub ahead of print].
- Gironacci MM, Cerniello FM, Longo Carbajosa NA, et al. Protective axis of the renin-angiotensin system in the brain. Clin Sci (Lond). 2014; 127(5): 295–306.
- Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11(8): 875–879.
- Xu P, Sriramula S, Lazartigues E. ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol. 2011; 300(4): R804–R817.
- Chen Ji, Zhao Y, Chen S, et al. Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology. 2014; 79: 550–558.
- Peña Silva RA, Chu Yi, Miller JD, et al. Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging. Stroke. 2012; 43(12): 3358–3363.
- Fumagalli S, Perego C, Pischiutta F, et al. The ischemic environment drives microglia and macrophage function. Front Neurol. 2015; 6: 81.
- Mukerji SS, Solomon IH. What can we learn from brain autopsies in COVID-19? Neurosci Lett. 2021; 742: 135528.
- Reichard RR, Kashani KB, Boire NA, et al. Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology. Acta Neuropathol. 2020; 140(1): 1–6.
- Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020; 16(11): 636–644.
- Hess DC, Eldahshan W, Rutkowski E. COVID-19-related stroke. Transl Stroke Res. 2020; 11(3): 322–325.
- Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18(4): 844–847.
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020; 395(10229): 1054–1062.
- Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020; 382(25): e102.
- Katal S, Balakrishnan S, Gholamrezanezhad A. Neuroimaging and neurologic findings in COVID-19 and other coronavirus infections: A systematic review in 116 patients. J Neuroradiol. 2021; 48(1): 43–50.
- Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020; 143(10): 3104–3120.
- Iba T, Warkentin TE, Thachil J, et al. Proposal of the definition for COVID-19-associated coagulopathy. J Clin Med. 2021; 10(2).
- Hamming I, Timens W, Bulthuis MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2): 631–637.
- Valderrama EV, Humbert K, Lord A, et al. Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke. Stroke. 2020; 51(7): e124–e127.
- Zhang B, Zhou X, Qiu Y, et al. Clinical characteristics of 82 cases of death from COVID-19. PLoS One. 2020; 15(7): e0235458.
- Zuo Yu, Zuo M, Yalavarthi S, et al. Neutrophil extracellular traps and thrombosis in COVID-19. J Thromb Thrombolysis. 2021; 51(2): 446–453.
- Pfeiler S, Massberg S, Engelmann B. Biological basis and pathological relevance of microvascular thrombosis. Thromb Res. 2014; 133 Suppl 1: S35–S37.
- Haidar MA, Jourdi H, Haj Hassan Z, et al. Neurological and neuropsychological changes associated with SARS-CoV-2 infection: new observations, new mechanisms. Neuroscientist. 2021 [Epub ahead of print]: 1073858420984106.
- Tisoncik JR, Korth MJ, Simmons CP, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012; 76(1): 16–32.
- Li Y, Fu Li, Gonzales DM, et al. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J Virol. 2004; 78(7): 3398–3406.
- Banks WA, Freed EO, Wolf KM, et al. Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol. 2001; 75(10): 4681–4691.
- Erickson MA, Banks WA. Neuroimmune axes of the blood-brain barriers and blood-brain interfaces: bases for physiological regulation, disease states, and pharmacological interventions. Pharmacol Rev. 2018; 70(2): 278–314.
- Heneka MT, Golenbock D, Latz E, et al. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020; 12(1): 69.
- Lindlau A, Widmann CN, Putensen C, et al. Predictors of hippocampal atrophy in critically ill patients. Eur J Neurol. 2015; 22(2): 410–415.
- Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev. 2018; 98(1): 477–504.
- Najjar S, Pahlajani S, De Sanctis V, et al. Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: a theoretical integration of clinical and experimental evidence. Front Psychiatry. 2017; 8: 83.
- de Candia P, Prattichizzo F, Garavelli S, et al. T Cells: Warriors of SARS-CoV-2 Infection. Trends Immunol. 2021; 42(1): 18–30.
- Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine. 2020; 8(4): 420–422.
- Song JW, Zhang C, Fan X, et al. Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nat Commun. 2020; 11(1): 3410.
- Diao Bo, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. 2020; 11: 827.
- Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020; 17(5): 533–535.
- Wu GF, Dandekar AA, Pewe L, et al. The role of CD4 and CD8 T cells in MHV-JHM-induced demyelination. Adv Exp Med Biol. 2001; 494: 341–347.
- Hung ECW, Chim SSC, Chan PKS, et al. Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome. Clin Chem. 2003; 49(12): 2108–2109.
- Yeh EA, Collins A, Cohen ME, et al. Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics. 2004; 113(1 Pt 1): e73–e76.
- Guo S, Som AT, Arai K, et al. Effects of angiotensin-II on brain endothelial cell permeability via PPARalpha regulation of para- and trans-cellular pathways. Brain Res. 2019; 1722: 146353.
- Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018; 314(1): L17–L31.
- Kempuraj D, Selvakumar GP, Ahmed ME, et al. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation. Neuroscientist. 2020; 26(5-6): 402–414.
- Park MD. Macrophages: a Trojan horse in COVID-19? Nat Rev Immunol. 2020; 20(6): 351.
- Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020; 277(8): 2251–2261.
- Brann DH, Tsukahara T, Weinreb C, et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020; 6(31).
- Li K, Wohlford-Lenane C, Perlman S, et al. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 2016; 213(5): 712–722.
- McCray PB, Pewe L, Wohlford-Lenane C, et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol. 2007; 81(2): 813–821.
- Dubé M, Le Coupanec A, Wong AHM, et al. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol. 2018; 92(17).
- Perlman S, Jacobsen G, Afifi A. Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves. Virology. 1989; 170(2): 556–560.
- Matsuda K, Park CH, Sunden Y, et al. The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol. 2004; 41(2): 101–107.
- Breit S, Kupferberg A, Rogler G, et al. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry. 2018; 9: 44.
- Muus C, Luecken MD, Eraslan G, et al. NHLBI LungMap Consortium, Human Cell Atlas Lung Biological Network. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat Med. 2021; 27(3): 546–559.
- Zubair AS, McAlpine LS, Gardin T, et al. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of Coronavirus Disease 2019: A review. JAMA Neurol. 2020; 77(8): 1018–1027.
