Involvement of the Nervous System in SARS-CoV-2 Infection

Hao Li, Qun Xue, Xingshun Xu, Hao Li, Qun Xue, Xingshun Xu

Abstract

As a severe and highly contagious infectious disease, coronavirus disease 2019 (COVID-19) has caused a global pandemic. Several case reports have demonstrated that the respiratory system is the main target in patients with COVID-19, but the disease is not limited to the respiratory system. Case analysis indicated that the nervous system can be invaded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and that 36.4% of COVID-19 patients had neurological symptoms. Importantly, the involvement of the CNS may be associated with poor prognosis and disease worsening. Here, we discussed the symptoms and evidence of nervous system involvement (directly and indirectly) caused by SARS-CoV-2 infection and possible mechanisms. CNS symptoms could be a potential indicator of poor prognosis; therefore, the prevention and treatment of CNS symptoms are also crucial for the recovery of COVID-19 patients.

Keywords: COVID-19; Central nervous system; Infection; SARS-CoV-2.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Possible mechanisms of SARS-CoV-2 infection-related CNS symptoms. a SARS-CoV-2 may enter the brain through the olfactory nerve endings and directly infect neurons via ACE2 protein on the surface of neurons. Axonal transport may promote the rapid spread of neurons to neurons. Also, cytokines secreted from infected neurons damage nearby neurons and glial cells. b SARS-CoV-2 may enter the blood vessels through mucosa and infected lungs. SARS-CoV-2 binds to ACE2 protein that is abundantly expressed in endothelial cells, disrupting endothelial cells and the blood-brain barrier and leading to cerebral edema and intracranial hypertension. c After SARS-CoV-2 infection, human immune cells produce antibodies against this coronavirus; however, some autoantibodies also attack endothelial cells of the vessels and neurons, resulting in autoimmune encephalitis. d Stress caused by panic or SARS-CoV-2 infection causes the release of corticotrophin-releasing hormone (CRF) as well as the activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the over-activation of the HPA axis effectors glucocorticoids and GR and exhibit different behaviors. At the same time, environmental stress causes epigenetic modification changes on stress-related genes and leads to abnormal gene expression. Therefore, environmental stress from COVID-19 pandemic can cause psychiatric conditions such as depression, anxiety, psychiatric symptoms, or posttraumatic stress disorder (PTSD)

References

    1. Arbour N, Côté G, Lachance C, Tardieu M, Cashman NR, Talbot PJ. Acute and persistent infection of human neural cell lines by human coronavirus OC43. J Virol. 1999;73:3338–3350. doi: 10.1128/JVI.73.4.3338-3350.1999.
    1. Bao Y, Sun Y, Meng S, Shi J, Lu L. 2019-nCoV epidemic: address mental health care to empower society. Lancet (London, England) 2020;395:e37–e38. doi: 10.1016/s0140-6736(20)30309-3.
    1. Beigel JH, Nam HH, Adams PL, Krafft A, Ince WL, El-Kamary SS, Sims AC. Advances in respiratory virus therapeutics - a meeting report from the 6th isirv Antiviral Group conference. Antiviral Res. 2019;167:45–67. doi: 10.1016/j.antiviral.2019.04.006.
    1. Bleau C, Filliol A, Samson M, Lamontagne L. Brain invasion by mouse hepatitis virus depends on impairment of tight junctions and beta interferon production in brain microvascular endothelial cells. J Virol. 2015;89:9896–9908. doi: 10.1128/jvi.01501-15.
    1. Bulut C, Kato Y. Epidemiology of COVID-19. Turk J Med Sci. 2020;50:563–570. doi: 10.3906/sag-2004-172.
    1. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9:221–236. doi: 10.1080/22221751.2020.1719902.
    1. Chen N, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England) 2020;395:507–513. doi: 10.1016/s0140-6736(20)30211-7.
    1. Chen Q, et al. Mental health care for medical staff in China during the COVID-19 outbreak. Lancet Psychiatry. 2020;7:e15–e16. doi: 10.1016/s2215-0366(20)30078-x.
    1. Cheng Y, et al. Ten-eleven translocation proteins modulate the response to environmental stress in mice. Cell Rep. 2018;25:3194–3203 e3194. doi: 10.1016/j.celrep.2018.11.061.
    1. Coronaviridae Study Group of the International Committee on Taxonomy of V The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536–544. doi: 10.1038/s41564-020-0695-z.
    1. Cowley TJ, Weiss SR. Murine coronavirus neuropathogenesis: determinants of virulence. J Neurovirol. 2010;16:427–434. doi: 10.3109/13550284.2010.529238.
    1. Curtin Niamh M., Boyle Noreen T., Mills Kingston H.G., Connor Thomas J. Psychological stress suppresses innate IFN-γ production via glucocorticoid receptor activation: Reversal by the anxiolytic chlordiazepoxide. Brain, Behavior, and Immunity. 2009;23(4):535–547. doi: 10.1016/j.bbi.2009.02.003.
    1. David T, Ling SF, Barton A. Genetics of immune-mediated inflammatory diseases. Clin Exp Immunol. 2018;193:3–12. doi: 10.1111/cei.13101.
    1. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19:269–301. doi: 10.1210/edrv.19.3.0331.
    1. Desforges Marc, Le Coupanec Alain, Brison Élodie, Meessen-Pinard Mathieu, Talbot Pierre J. Advances in Experimental Medicine and Biology. New Delhi: Springer India; 2014. Neuroinvasive and Neurotropic Human Respiratory Coronaviruses: Potential Neurovirulent Agents in Humans; pp. 75–96.
    1. Ding Y, Dai J. Advance in stress for depressive disorder. Adv Exp Med Biol. 2019;1180:147–178. doi: 10.1007/978-981-32-9271-0_8.
    1. Ding Y, 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;203:622–630. doi: 10.1002/path.1560.
    1. Du L, J. Zhao, Y. Shi, Y. Xi, G.G. Zheng, Y. Yi, and W.P. He (n.d.) A report of 4 cases of severe acute respiratory syndrome patients with suicide tendency. Academic Journal of Second Military Medical University
    1. Duan L, Zhu G. Psychological interventions for people affected by the COVID-19 epidemic. Lancet Psychiatry. 2020;7:300–302. doi: 10.1016/s2215-0366(20)30073-0.
    1. Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M, Talbot PJ (2018) Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol:92. 10.1128/jvi.00404-18
    1. Dubey D, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83:166–177. doi: 10.1002/ana.25131.
    1. Futch HS, Croft CL, Truong VQ, Krause EG, Golde TE. Targeting psychologic stress signaling pathways in Alzheimer’s disease. Mol Neurodegener. 2017;12:49. doi: 10.1186/s13024-017-0190-z.
    1. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14:72–73. doi: 10.5582/bst.2020.01047.
    1. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243–251. doi: 10.1038/nri1571.
    1. 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;203:631–637. doi: 10.1002/path.1570.
    1. Herman JP, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603–621. doi: 10.1002/cphy.c150015.
    1. Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.e278. doi: 10.1016/j.cell.2020.02.052.
    1. Hu HJ, Li N (2020) Thirty latest judgments of new coronary pneumonia. Accessed 29 Feb 2020.
    1. Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020;395:497–506. doi: 10.1016/s0140-6736(20)30183-5.
    1. Huang JZ, Han MF, Luo TD, Ren AK, Zhou XP. Mental health survey of 230 medical staff in a tertiary infectious disease hospital for COVID-19. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases. 2020;38:E001. doi: 10.3760/cma.j.cn121094-20200219-00063.
    1. Kang L, et al. The mental health of medical workers in Wuhan, China dealing with the 2019 novel coronavirus. Lancet Psychiatry. 2020;7:e14. doi: 10.1016/s2215-0366(20)30047-x.
    1. Karagianni P., Alexopoulos H., Sourdi A., Papadimitriou D., Dimitrakopoulos A.N., Moutsopoulos H.M. West Nile Virus infection triggering autoimmune encephalitis: Pathophysiological and therapeutic implications. Clinical Immunology. 2019;207:97–99. doi: 10.1016/j.clim.2019.07.007.
    1. Kumar A, Rinwa P, Kaur G, Machawal L. Stress: neurobiology, consequences and management. J Pharm Bioallied Sci. 2013;5:91–97. doi: 10.4103/0975-7406.111818.
    1. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 2020;55:105924. doi: 10.1016/j.ijantimicag.2020.105924.
    1. Lai J, et al. Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019. JAMA Network Open. 2020;3:e203976–e203976. doi: 10.1001/jamanetworkopen.2020.3976.
    1. Li Yan‐Chao, Bai Wan‐Zhu, Hashikawa Tsutomu. The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients. Journal of Medical Virology. 2020;92(6):552–555. doi: 10.1002/jmv.25728.
    1. Lin YS, et al. Antibody to severe acute respiratory syndrome (SARS)-associated coronavirus spike protein domain 2 cross-reacts with lung epithelial cells and causes cytotoxicity. Clin Exp Immunol. 2005;141:500–508. doi: 10.1111/j.1365-2249.2005.02864.x.
    1. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 10.1001/jamaneurol.2020.1127
    1. Maunder RG. Was SARS a mental health catastrophe? Gen Hosp Psychiatry. 2009;31:316–317. doi: 10.1016/j.genhosppsych.2009.04.004.
    1. Moriguchi Takeshi, Harii Norikazu, Goto Junko, Harada Daiki, Sugawara Hisanori, Takamino Junichi, Ueno Masateru, Sakata Hiroki, Kondo Kengo, Myose Natsuhiko, Nakao Atsuhito, Takeda Masayuki, Haro Hirotaka, Inoue Osamu, Suzuki-Inoue Katsue, Kubokawa Kayo, Ogihara Shinji, Sasaki Tomoyuki, Kinouchi Hiroyuki, Kojin Hiroyuki, Ito Masami, Onishi Hiroshi, Shimizu Tatsuya, Sasaki Yu, Enomoto Nobuyuki, Ishihara Hiroshi, Furuya Shiomi, Yamamoto Tomoko, Shimada Shinji. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases. 2020;94:55–58. doi: 10.1016/j.ijid.2020.03.062.
    1. Noisakran S, Halford WP, Veress L, Carr DJ. Role of the hypothalamic pituitary adrenal axis and IL-6 in stress-induced reactivation of latent herpes simplex virus type 1. J Immunol. 1998;160:5441–5447.
    1. Patel A, Jernigan DB. Initial public health response and interim clinical guidance for the 2019 novel coronavirus outbreak - United States, December 31, 2019-February 4, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:140–146. doi: 10.15585/mmwr.mm6905e1.
    1. Petersen E, et al. Li Wenliang, a face to the frontline healthcare worker. The first doctor to notify the emergence of the SARS-CoV-2, (COVID-19), outbreak. Int J Infect Dis. 2020;93:205–207. doi: 10.1016/j.ijid.2020.02.052.
    1. Prasad Alisha, Chaichi Ardalan, Kelley D. Parker, Francis Joseph, Gartia Manas Ranjan. Current and future functional imaging techniques for post-traumatic stress disorder. RSC Advances. 2019;9(42):24568–24594. doi: 10.1039/C9RA03562A.
    1. Ryan J, Chaudieu I, Ancelin ML, Saffery R. Biological underpinnings of trauma and post-traumatic stress disorder: focusing on genetics and epigenetics. Epigenomics. 2016;8:1553–1569. doi: 10.2217/epi-2016-0083.
    1. Sanders J, Nemeroff C. The CRF system as a therapeutic target for neuropsychiatric disorders trends. Pharmacol Sci. 2016;37:1045–1054. doi: 10.1016/j.tips.2016.09.004.
    1. Skinner D, Marro BS, Lane TE. Chemokine CXCL10 and coronavirus-induced neurologic disease. Viral Immunol. 2019;32:25–37. doi: 10.1089/vim.2018.0073.
    1. Skopouli FN, Katsiougiannis S. How stress contributes to autoimmunity-lessons from Sjögren’s syndrome. FEBS Lett. 2018;592:5–14. doi: 10.1002/1873-3468.12933.
    1. Soria V, et al. Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis. Psychoneuroendocrinology. 2018;93:8–19. doi: 10.1016/j.psyneuen.2018.04.012.
    1. Tong ZD, et al. Potential presymptomatic transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis. 2020;26:1052–1054. doi: 10.3201/eid2605.200198.
    1. 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;323:1061. doi: 10.1001/jama.2020.1585.
    1. Wu F, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579:265–269. doi: 10.1038/s41586-020-2008-3.
    1. Xiang P et al (2020) First case of 2019 novel coronavirus disease with encephalitis. ChinaXiv T20200300015
    1. Xiao H, Zhang Y, Kong D, Li S, Yang N. The effects of social support on sleep quality of medical staff treating patients with coronavirus disease 2019 (COVID-19) in January and February 2020 in China. Medical science monitor : international medical journal of experimental and clinical research. 2020;26:e923549. doi: 10.12659/msm.923549.
    1. Xu K et al (2020a) Management of corona virus disease-19 (COVID-19): the Zhejiang experience. Zhejiang da xue xue bao Yi xue ban = journal of Zhejiang University medical sciences 49
    1. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB, Wang HY, Zhang S, Gao HN, Sheng JF, Cai HL, Qiu YQ, Li LJ. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606. doi: 10.1136/bmj.m606.
    1. Yan C, et al. Disturbed yin-Yang balance: stress increases the susceptibility to primary and recurrent infections of herpes simplex virus type 1. Acta Pharm Sin B. 2020;10:383–398. doi: 10.1016/j.apsb.2019.06.005.
    1. Yang SL, Liu LJ, Dai L, Zhang C, Li JT, Chen C, Liu H. Analysis of anxiety in 78 SARS patients. Nanfang Journal of Nursing. 2003;10:27–28.
    1. Yang YH, Huang YH, Chuang YH, Peng CM, Wang LC, Lin YT, Chiang BL. Autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome (SARS)-associated coronavirus infection. J Med Virol. 2005;77:1–7. doi: 10.1002/jmv.20407.
    1. Zhang L, Liu Y. Potential interventions for novel coronavirus in China: a systematic review. J Med Virol. 2020;92:479–490. doi: 10.1002/jmv.25707.
    1. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, Gao YD (2020) Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 10.1111/all.14238
    1. Zhou P, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi: 10.1038/s41586-020-2012-7.
    1. Zou L, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382:1177–1179. doi: 10.1056/NEJMc2001737.

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