Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.

Keywords

coronavirus disease 2019 (COVID-19) / SARS-CoV-2 / neurological manifestations / neuroinvasion / brain

References

[1] Sun P, Qie S, Liu Z, Ren J, Li K, Xi J. Clinical characteristics of hospitalized patients with SARS‐CoV‐2 infection: a single arm meta‐analysis. J Med Virol 2020 Feb 28. [Epub ahead of print] doi: 10.1002/jmv.25735

[2] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 Feb 7. [Epub ahead of print] doi: 10.1001/jama.2020.1585

[3] National Health Commission of the People’s Republic of China. The guidelines for the diagnosis and treatment of novel coronavirus (2019-nCoV) infection (trial version 7). 2020. http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml (in Chinese) (accessed March 4, 2020)

[4] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513

[5] Mao L, Wang MD, Chen SH, He QW, Chang J, Hong CD, Zhou YF, Wang D, Li YN, Jin HJ, Hu B. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv 2020; doi: 10.1101/2020.02.22.20026500

[6] Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19patients. J Med Virol 2020 Feb 27. [Epub ahead of print] doi: 10.1002/jmv.25728

[7] Grifoni A, Sidney J, Zhang Y, Scheuermann RH, Peters B, Sette A. A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2. Cell Host Microbe 2020 Mar 16. [Epub ahead of print] doi：10.1016/j.chom.2020.03.002

[8] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, 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 Mar 4. [Epub ahead of print] doi: 10.1016/j.cell.2020.02.052

[9] Abiodun OA, Ola MS. Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci 2020; 27(3): 905–912

[10] Sasannejad C, Ely EW, Lahiri S. Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms. Crit Care 2019; 23(1): 352

[11] Harnisch LO, Riech S, Mueller M, Gramueller V, Quintel M, Moerer O. Longtime neurologic outcome of extracorporeal membrane oxygenation and non extracorporeal membrane oxygenation acute respiratory distress syndrome survivors. J Clin Med 2019; 8(7): E1020

[12] Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020 Mar 4. [Epub ahead of print] doi: 10.1016/S2468-1253(20)30057-1

[13] Jiang F, Deng L, Zhang L, Cai Y, Cheung CW, Xia Z. Review of the clinical characteristics of coronavirus disease 2019 (COVID-19). J Gen Intern Med 2020 Mar 4. [Epub ahead of print] doi: 10.1007/s11606-020-05762-w

[14] Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 2004; 173(6): 4030–4039

[15] Li YC, Bai WZ, Hirano N, Hayashida T, Hashikawa T. Coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer, and the early response of satellite cells. Virus Res 2012; 163(2): 628–635

[16] Li YC, Bai WZ, Hirano N, Hayashida T, Taniguchi T, Sugita Y, Tohyama K, Hashikawa T. Neurotropic virus tracing suggests a membranous-coating-mediated mechanism for transsynaptic communication. J Comp Neurol 2013; 521(1): 203–212

[17] Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr. 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

[18] Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M, Talbot PJ. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol 2018; 92(17): e00404-18

[19] Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 2008; 82(15): 7264–7275

[20] Lochhead JJ, Kellohen KL, Ronaldson PT, Davis TP. Distribution of insulin in trigeminal nerve and brain after intranasal administration. Sci Rep 2019; 9(1): 2621

[21] Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012; 64(7): 614–628

[22] Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, Wang H, Shen H, Qiu L, Li Z, Geng J, Cai J, Han H, Li X, Kang W, Weng D, Liang P, Jiang S. 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

[23] Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, Zhuang H, Wu B, Zhong H, Shao H, Fang W, Gao D, Pei F, Li X, He Z, Xu D, Shi X, Anderson VM, Leong AS. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005; 202(3): 415–424

[24] Xu J, Zhong S, Liu J, Li L, Li Y, Wu X, Li Z, Deng P, Zhang J, Zhong N, Ding Y, Jiang Y. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine Mig in pathogenesis. Clin Infect Dis 2005; 41(8): 1089–1096

[25] Sun XF, Zhang X, Chen XH, Chen LW, Deng CH, Zou XJ, Liu WY, Yu HM. The infection evidence of SARS-COV-2 in ocular surface: a single-center cross-sectional study. medRxiv 2020; doi: 10.1101/2020.02.26.20027938

[26] Baig AM, Khaleeq A, Ali U, Syeda H. 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

[27] Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996; 9(3): 361–381

[28] Cohen JI. Varicella-zoster virus. The virus. Infect Dis Clin North Am 1996; 10(3): 457–468

[29] Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495(7440): 251–254

[30] Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 2020 Mar 19. [Epub ahead of print] doi: 10.1016/j.bbrc.2020.03.044

[31] Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237–261

[32] Simmons G, Zmora P, Gierer S, Heurich A, Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res 2013; 100(3): 605–614

[33] Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260–1263

[34] Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol 2008; 93(5): 543–548

[35] Li Z, Wu M, Yao JW, Guo J, Liao X, Song SJ, Li JL, Duan GJ, Zhou YX, Wu XJ, Zhou ZS, Wang TJ, Hu M, Chen XX, Fu Y, Lei C, Dong HL, Xu CO, Hu YH, Han M, Zhou Y, Jia HB, Chen XW, Yan JA. Caution on kidney dysfunctions of COVID-19 patients. medRxiv 2020; doi: 10.1101/2020.02.08.20021212

[36] Xu H, Hou K, Xu H, Li Z, Chen H, Zhang N, Xu R, Fu H, Sun R, Wen L, Xie L, Liu H, Zhang K, Selvanayagam JB, Fu C, Zhao S, Yang Z, Yang M, Guo Y. Acute myocardial injury of patients with coronavirus disease 2019. medRxiv 2020; doi:10.1101/2020.03.05.20031591

[37] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506

[38] Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. 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

[39] Henry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc Bayl Univ Med Cent 2018; 31(4): 419–423

[40] Moore MJ, Dorfman T, Li W, Wong SK, Li Y, Kuhn JH, Coderre J, Vasilieva N, Han Z, Greenough TC, Farzan M, Choe H. Retroviruses pseudotyped with the severe acute respiratory syndrome coronavirus spike protein efficiently infect cells expressing angiotensin-converting enzyme 2. J Virol 2004; 78(19): 10628–10635

[41] Tan WSD, Liao W, Zhou S, Mei D, Wong WF. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr Opin Pharmacol 2018; 40: 9–17

[42] Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, Li J, Zhao D, Xu D, Gong Q, Liao J, Yang H, Hou W, Zhang Y. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395(10226): 809–815

[43] Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C, Hui D SC, Du B, Li L, Zeng G, Yuen KY, Chen R, Tang C, Wang T, Chen P, Xiang J, Li S, Wang J, Liang Z, Peng Y, Wei L, Liu Y, Hu Y, Peng P, Wang J, Liu J, Chen Z, Li G, Zheng Z, Qiu S, Luo J, Ye C, Zhu S, Zhong N. Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv 2020; doi: 10.1101/2020.02.06.20020974

[44] Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, Diaz G, Cohn A, Fox L, Patel A, Gerber SI, Kim L, Tong S, Lu X, Lindstrom S, Pallansch MA, Weldon WC, Biggs HM, Uyeki TM, Pillai SK; Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382(10): 929–936

[45] Xiao F, Tang M, Zheng X, Li C, He J, Hong Z, Huang S, Zhang Z, Lin X, Fang Z, Lai R, Chen S, Liu J, Huang J, Xia J, Li Z, Jiang G, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. medRxiv 2020; doi: 10.1101/2020.02.17.20023721

[46] Chen H, Xuan B, Yan Y, Zhu X, Shen C, Zhao G, Ji L, Xu D, Xiong H, Yu TC, Li X, Liu Q, Chen Y, Cui Y, Hong J, Fang JY. Profiling ACE2 expression in colon tissue of healthy adults and colorectal cancer patients by single-cell transcriptome analysis. medRxiv 2020; doi: 10.1101/2020.02.15.20023457

[47] Li H, Wu C, Yang Y, Liu Y, Zhang P, Wang Y, Wang Q, Xu Y, Li M, Zheng M, Chen L. Furin, a potential therapeutic target for COVID-19. chinaXiv 2020; http://chinaxiv.org/abs/202002.00062

[48] Li W, Zhu Y, Li Y, Shu M, Wen Y, Gao X, Wan C. The gut microbiota of hand, foot and mouth disease patients demonstrates down-regulated butyrate-producing bacteria and up-regulated inflammation-inducing bacteria. Acta Paediatr 2019; 108(6): 1133–1139

[49] Chen L, Li L, Han Y, Lv B, Zou S, Yu Q. Tong-fu-li-fei decoction exerts a protective effect on intestinal barrier of sepsis in rats through upregulating ZO-1/occludin/claudin-1 expression. J Pharmacol Sci 2020 Feb 28. [Epub ahead of print] doi: 10.1016/j.jphs.2020.02.009

[50] Fernández-Blanco JA, Estévez J, Shea-Donohue T, Martínez V, Vergara P. Changes in epithelial barrier function in response to parasitic infection: implications for IBD pathogenesis. J Crohn’s Colitis 2015; 9(6): 463–476

[51] Romani L, Del Chierico F, Chiriaco M, Foligno S, Reddel S, Salvatori G, Cifaldi C, Faraci S, Finocchi A, Rossi P, Bagolan P, D’Argenio P, Putignani L, Fusaro F. Gut mucosal and fecal microbiota profiling combined to intestinal immune system in neonates affected by intestinal ischemic injuries. Front Cell Infect Microbiol 2020; 10: 59

[52] Khoury-Hanold W, Yordy B, Kong P, Kong Y, Ge W, Szigeti-Buck K, Ralevski A, Horvath TL, Iwasaki A. Viral spread to enteric neurons links genital HSV-1 infection to toxic megacolon and lethality. Cell Host Microbe 2016; 19(6): 788–799

[53] Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, Kida H, Umemura T. The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 2004; 41(2): 101–107

[54] Hosseini S, Wilk E, Michaelsen-Preusse K, Gerhauser I, Baumgärtner W, Geffers R, Schughart K, Korte M. Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function. J Neurosci 2018; 38(12): 3060–3080

[55] Zhao JM, Zhou GD, Sun YL, Wang SS, Yang JF, Meng EH, Pan D, Li WS, Zhou XS, Wang YD, Lu JY, Li N, Wang DW, Zhou BC, Zhang TH. Clinical pathology and pathogenesis of severe acute respiratory syndrome. Chin J Exp Clin Virol (Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi) 2003; 17(3): 217–221 (in Chinese)

[56] Xiao Y, Meng Q, Yin X, Guan Y, Liu Y, Li C, Wang M, Liu G, Tong T, Wang LF, Kong X, Wu D. Pathological changes in masked palm civets experimentally infected by severe acute respiratory syndrome (SARS) coronavirus. J Comp Pathol 2008; 138(4): 171–179

[57] Yucel Y, Gupta N. Lymphatic drainage from the eye: a new target for therapy. Prog Brain Res 2015; 220: 185–198

[58] Zhang Z, Helman JI, Li LJ. Lymphangiogenesis, lymphatic endothelial cells and lymphatic metastasis in head and neck cancer—a review of mechanisms. Int J Oral Sci 2010; 2(1): 5–14

[59] Nedumpun T, Sirisereewan C, Thanmuan C, Techapongtada P, Puntarotairung R, Naraprasertkul S, Thanawongnuwech R, Suradhat S. Induction of porcine reproductive and respiratory syndrome virus (PRRSV)-specific regulatory T lymphocytes (Treg) in the lungs and tracheobronchial lymph nodes of PRRSV-infected pigs. Vet Microbiol 2018; 216: 13–19

[60] Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV. Redox biology of respiratory viral infections. Viruses 2018; 10(8): E392

[61] McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 2007; 81(2): 813–821

[62] Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523(7560): 337–341

[63] Cheng Y, Haorah J. How does the brain remove its waste metabolites from within? Int J Physiol Pathophysiol Pharmacol 2019; 11(6): 238–249

[64] Cashion MF, Banks WA, Bost KL, Kastin AJ. Transmission routes of HIV-1 gp120 from brain to lymphoid tissues. Brain Res 1999; 822(1-2): 26–33

[65] Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2010; 99(4): 1654–1673

Acknowledgements

This work is funded by the National Natural Science Foundation of China (Nos. 81873726, 81971012, and 81901095), Peking University “Clinical Medicine plus X” Youth Project (No. PKU2020LCXQ016) and Key Clinical Projects of Peking University Third Hospital (No. BYSYZD2019027). We acknowledge all healthcare workers involved in the diagnosis and treatment of COVID-19 patients all around China. We acknowledge Edanz Group for the linguistic editing and proofreading during the preparation of this manuscript.

Compliance with ethics guidelines

Zhengqian Li, Taotao Liu, Ning Yang, Dengyang Han, Xinning Mi, Yue Li, Kaixi Liu, Alain Vuylsteke, Hongbing Xiang, and Xiangyang Guo declare no conflicts of interest. This manuscript is a review and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2020 Higher Education Press