Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2020, Vol. 14 Issue (5) : 533-541    https://doi.org/10.1007/s11684-020-0786-5
REVIEW
Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain
Zhengqian Li1, Taotao Liu1, Ning Yang1, Dengyang Han1, Xinning Mi1, Yue Li1, Kaixi Liu1, Alain Vuylsteke2, Hongbing Xiang3(), Xiangyang Guo1()
1. Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
2. Department of Anaesthesia and Intensive Care, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
3. Department of Anesthesiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
 Download: PDF(525 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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     
Corresponding Author(s): Hongbing Xiang,Xiangyang Guo   
Just Accepted Date: 04 April 2020   Online First Date: 07 May 2020    Issue Date: 12 October 2020
 Cite this article:   
Zhengqian Li,Taotao Liu,Ning Yang, et al. Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain[J]. Front. Med., 2020, 14(5): 533-541.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0786-5
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I5/533
Fig.1  The main organs and potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. SARS-CoV-2 binds to angiotensin-converting enzyme type 2, which is widely distributed in the lungs, heart, liver, kidney, and intestine. SARS-CoV-2 induces the intrinsic immune response, a cytokine storm, acute respiratory distress syndrome, and damages peripheral tissues. It may simultaneously invade the brain through the vascular, peripheral nerve, lymphatics, and cerebrospinal fluid pathways. Consequently, the brain may be involved in the systemic response after being subjected to hypoxemia.
Fig.2  Potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. Inhalation droplets and close contact transmission are the main person-to-person transmission routes of COVID-19. Once the virus enters a host cell, the innate immune response may trigger a cytokine storm, especially under profound hypoxemia conditions induced by ARDS in patients with severe COVID-19. (i) When SARS-CoV-2-carrying droplets contact the eye conjunctiva, they can enter the brain after infecting the trigeminal nerve (V), resulting in decreased vision. (ii) The virus may also infect the sensory neurons in the taste buds, ascend to the nucleus of the solitary tract (VII, IX, and X) or trigeminal nerve (V) and enter the CNS through neuronal retrograde transport. (iii) Once the virus-containing droplets land on the nasal mucosa, SARS-CoV-2 may enter the brain along the olfactory nerve. In addition, the abundant capillary blood vessels and lymphatics underlying the nasal mucosa provide opportunities for virus invasion. (iv) Viruses that enter the respiratory tract flow into the bloodstream through ACE2 receptors expressed in the epithelial cells of the respiratory tract. In addition to the vascular pathways, the virus spreads toward the CNS through the vagus nerve branch (X) that innervates the respiratory tract, resulting in dry cough, dyspnea, and exacerbating acute respiratory distress syndrome. (v) Similarly, poor hand hygiene gives the virus the opportunity to enter the gastrointestinal tract and then enter the brain through the vasculature, vagus nerve, and lymphoid pathways. These patients may experience loss of appetite, nausea, vomiting, and diarrhea. (vi) The virus that enters the circulation can invade the brain through the damaged BBB and leak into the interstitial fluid, and then enter the cerebral spinal fluid through the intracerebral lymphatic circulation. Viruses in the blood can also enter the fourth ventricle directly through a damaged blood cerebral spinal fluid barrier.
1 P Sun, S Qie, Z Liu, J Ren, K Li, J Xi. 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
https://doi.org/10.1002/jmv.25735
2 D Wang, B Hu, C Hu, F Zhu, X Liu, J Zhang, B Wang, H Xiang, Z Cheng, Y Xiong, Y Zhao, Y Li, X Wang, Z Peng. 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
https://doi.org/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. (in Chinese) (accessed March 4, 2020)
4 N Chen, M Zhou, X Dong, J Qu, F Gong, Y Han, Y Qiu, J Wang, Y Liu, Y Wei, J Xia, T Yu, X Zhang, L Zhang. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513
https://doi.org/10.1016/S0140-6736(20)30211-7 pmid: 32007143
5 L Mao, MD Wang, SH Chen, QW He, J Chang, CD Hong, YF Zhou, D Wang, YN Li, HJ Jin, B Hu. 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
https://doi.org/10.1101/2020.02.22.20026500
6 YC Li, WZ Bai, T Hashikawa. 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
https://doi.org/10.1002/jmv.25728
7 A Grifoni, J Sidney, Y Zhang, RH Scheuermann, B Peters, A Sette. 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
https://doi.org/10.1016/j.chom.2020.03.002
8 M Hoffmann, H Kleine-Weber, S Schroeder, N Krüger, T Herrler, S Erichsen, TS Schiergens, G Herrler, NH Wu, A Nitsche, MA Müller, C Drosten, S Pöhlmann. 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
https://doi.org/10.1016/j.cell.2020.02.052 pmid: 32142651
9 OA Abiodun, MS Ola. Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci 2020; 27(3): 905–912
https://doi.org/10.1016/j.sjbs.2020.01.026 pmid: 32127770
10 C Sasannejad, EW Ely, S Lahiri. Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms. Crit Care 2019; 23(1): 352
https://doi.org/10.1186/s13054-019-2626-z pmid: 31718695
11 LO Harnisch, S Riech, M Mueller, V Gramueller, M Quintel, O Moerer. Longtime neurologic outcome of extracorporeal membrane oxygenation and non extracorporeal membrane oxygenation acute respiratory distress syndrome survivors. J Clin Med 2019; 8(7): E1020
https://doi.org/10.3390/jcm8071020 pmid: 31336827
12 C Zhang, L Shi, FS Wang. 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
https://doi.org/10.1016/S2468-1253(20)30057-1 pmid: 32145190
13 F Jiang, L Deng, L Zhang, Y Cai, CW Cheung, Z Xia. 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
https://doi.org/10.1007/s11606-020-05762-w pmid: 32133578
14 WG Glass, K Subbarao, B Murphy, PM Murphy. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 2004; 173(6): 4030–4039
https://doi.org/10.4049/jimmunol.173.6.4030 pmid: 15356152
15 YC Li, WZ Bai, N Hirano, T Hayashida, T Hashikawa. 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
https://doi.org/10.1016/j.virusres.2011.12.021 pmid: 22248641
16 YC Li, WZ Bai, N Hirano, T Hayashida, T Taniguchi, Y Sugita, K Tohyama, T Hashikawa. Neurotropic virus tracing suggests a membranous-coating-mediated mechanism for transsynaptic communication. J Comp Neurol 2013; 521(1): 203–212
https://doi.org/10.1002/cne.23171 pmid: 22700307
17 K Li, C Wohlford-Lenane, S Perlman, J Zhao, AK Jewell, LR Reznikov, KN Gibson-Corley, DK Meyerholz, PB McCray 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
https://doi.org/10.1093/infdis/jiv499 pmid: 26486634
18 M Dubé, A Le Coupanec, AHM Wong, JM Rini, M Desforges, PJ Talbot. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol 2018; 92(17): e00404-18
https://doi.org/10.1128/JVI.00404-18 pmid: 29925652
19 J Netland, DK Meyerholz, S Moore, M Cassell, S Perlman. 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
https://doi.org/10.1128/JVI.00737-08 pmid: 18495771
20 JJ Lochhead, KL Kellohen, PT Ronaldson, TP Davis. Distribution of insulin in trigeminal nerve and brain after intranasal administration. Sci Rep 2019; 9(1): 2621
https://doi.org/10.1038/s41598-019-39191-5 pmid: 30796294
21 JJ Lochhead, RG Thorne. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012; 64(7): 614–628
https://doi.org/10.1016/j.addr.2011.11.002 pmid: 22119441
22 Y Ding, L He, Q Zhang, Z Huang, X Che, J Hou, H Wang, H Shen, L Qiu, Z Li, J Geng, J Cai, H Han, X Li, W Kang, D Weng, P Liang, S Jiang. 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
https://doi.org/10.1002/path.1560 pmid: 15141376
23 J Gu, E Gong, B Zhang, J Zheng, Z Gao, Y Zhong, W Zou, J Zhan, S Wang, Z Xie, H Zhuang, B Wu, H Zhong, H Shao, W Fang, D Gao, F Pei, X Li, Z He, D Xu, X Shi, VM Anderson, AS Leong. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005; 202(3): 415–424
https://doi.org/10.1084/jem.20050828 pmid: 16043521
24 J Xu, S Zhong, J Liu, L Li, Y Li, X Wu, Z Li, P Deng, J Zhang, N Zhong, Y Ding, Y Jiang. 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
https://doi.org/10.1086/444461 pmid: 16163626
25 XF Sun, X Zhang, XH Chen, LW Chen, CH Deng, XJ Zou, WY Liu, HM. Yu 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
https://doi.org/10.1101/2020.02.26.20027938
26 AM Baig, A Khaleeq, U Ali, H Syeda. 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
https://doi.org/10.1021/acschemneuro.0c00122 pmid: 32167747
27 AM Arvin. Varicella-zoster virus. Clin Microbiol Rev 1996; 9(3): 361–381
https://doi.org/10.1128/CMR.9.3.361 pmid: 8809466
28 JI Cohen. Varicella-zoster virus. The virus. Infect Dis Clin North Am 1996; 10(3): 457–468
https://doi.org/10.1016/S0891-5520(05)70308-1 pmid: 8856347
29 VS Raj, H Mou, SL Smits, DH Dekkers, MA Müller, R Dijkman, D Muth, JA Demmers, A Zaki, RA Fouchier, V Thiel, C Drosten, PJ Rottier, AD Osterhaus, BJ Bosch, BL Haagmans. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495(7440): 251–254
https://doi.org/10.1038/nature12005 pmid: 23486063
30 F Qi, S Qian, S Zhang, Z Zhang. 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
https://doi.org/10.1016/j.bbrc.2020.03.044
31 F Li. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3(1): 237–261
https://doi.org/10.1146/annurev-virology-110615-042301 pmid: 27578435
32 G Simmons, P Zmora, S Gierer, A Heurich, S Pöhlmann. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res 2013; 100(3): 605–614
https://doi.org/10.1016/j.antiviral.2013.09.028 pmid: 24121034
33 D Wrapp, N Wang, KS Corbett, JA Goldsmith, CL Hsieh, O Abiona, BS Graham, JS McLellan. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260–1263
https://doi.org/10.1126/science.abb2507 pmid: 32075877
34 Y Imai, K Kuba, JM Penninger. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol 2008; 93(5): 543–548
https://doi.org/10.1113/expphysiol.2007.040048 pmid: 18448662
35 Z Li, M Wu, JW Yao, J Guo, X Liao, SJ Song, JL Li, GJ Duan, YX Zhou, XJ Wu, ZS Zhou, TJ Wang, M Hu, XX Chen, Y Fu, C Lei, HL Dong, CO Xu, YH Hu, M Han, Y Zhou, HB Jia, XW Chen, JA Yan. Caution on kidney dysfunctions of COVID-19 patients. medRxiv 2020; doi: 10.1101/2020.02.08.20021212
https://doi.org/10.1101/2020.02.08.20021212
36 H Xu, K Hou, H Xu, Z Li, H Chen, N Zhang, R Xu, H Fu, R Sun, L Wen, L Xie, H Liu, K Zhang, JB Selvanayagam, C Fu, S Zhao, Z Yang, M Yang, Y Guo. Acute myocardial injury of patients with coronavirus disease 2019. medRxiv 2020; doi:10.1101/2020.03.05.20031591
https://doi.org/10.1101/2020.03.05.20031591
37 C Huang, Y Wang, X Li, L Ren, J Zhao, Y Hu, L Zhang, G Fan, J Xu, X Gu, Z Cheng, T Yu, J Xia, Y Wei, W Wu, X Xie, W Yin, H Li, M Liu, Y Xiao, H Gao, L Guo, J Xie, G Wang, R Jiang, Z Gao, Q Jin, J Wang, B Cao. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506
https://doi.org/10.1016/S0140-6736(20)30183-5 pmid: 31986264
38 I Hamming, W Timens, ML Bulthuis, AT Lely, G Navis, H van Goor. 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
https://doi.org/10.1002/path.1570 pmid: 15141377
39 C Henry, M Zaizafoun, E Stock, S Ghamande, AC Arroliga, HD White. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc Bayl Univ Med Cent 2018; 31(4): 419–423
https://doi.org/10.1080/08998280.2018.1499293 pmid: 30948970
40 MJ Moore, T Dorfman, W Li, SK Wong, Y Li, JH Kuhn, J Coderre, N Vasilieva, Z Han, TC Greenough, M Farzan, H Choe. 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
https://doi.org/10.1128/JVI.78.19.10628-10635.2004 pmid: 15367630
41 WSD Tan, W Liao, S Zhou, D Mei, WF Wong. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr Opin Pharmacol 2018; 40: 9–17
https://doi.org/10.1016/j.coph.2017.12.002 pmid: 29288933
42 H Chen, J Guo, C Wang, F Luo, X Yu, W Zhang, J Li, D Zhao, D Xu, Q Gong, J Liao, H Yang, W Hou, Y Zhang. 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
https://doi.org/10.1016/S0140-6736(20)30360-3 pmid: 32151335
43 W Guan, Z Ni, Y Hu, W Liang, C Ou, J He, L Liu, H Shan, C Lei, SC Hui D, B Du, L Li, G Zeng, KY Yuen, R Chen, C Tang, T Wang, P Chen, J Xiang, S Li, J Wang, Z Liang, Y Peng, L Wei, Y Liu, Y Hu, P Peng, J Wang, J Liu, Z Chen, G Li, Z Zheng, S Qiu, J Luo, C Ye, S Zhu, N Zhong. Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv 2020; doi: 10.1101/2020.02.06.20020974
https://doi.org/10.1101/2020.02.06.20020974
44 ML Holshue, C DeBolt, S Lindquist, KH Lofy, J Wiesman, H Bruce, C Spitters, K Ericson, S Wilkerson, A Tural, G Diaz, A Cohn, L Fox, A Patel, SI Gerber, L Kim, S Tong, X Lu, S Lindstrom, MA Pallansch, WC Weldon, HM Biggs, TM Uyeki, SK Pillai; 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
https://doi.org/10.1056/NEJMoa2001191 pmid: 32004427
45 F Xiao, M Tang, X Zheng, C Li, J He, Z Hong, S Huang, Z Zhang, X Lin, Z Fang, R Lai, S Chen, J Liu, J Huang, J Xia, Z Li, G Jiang, Y Liu, X Li, H Shan. Evidence for gastrointestinal infection of SARS-CoV-2. medRxiv 2020; doi: 10.1101/2020.02.17.20023721
https://doi.org/10.1101/2020.02.17.20023721
46 H Chen, B Xuan , Y Yan, X Zhu, C Shen, G Zhao , L Ji , D Xu, H Xiong, TC Yu, X Li, Q Liu, Y Chen, Y Cui, J Hong, JY Fang. 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
https://doi.org/10.1101/2020.02.15.20023457
47 H Li, C Wu, Y Yang, Y Liu, P Zhang, Y Wang, Q Wang, Y Xu , M Li, M Zheng, L Chen. Furin, a potential therapeutic target for COVID-19. chinaXiv 2020;
48 W Li, Y Zhu, Y Li, M Shu, Y Wen, X Gao, C Wan. 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
https://doi.org/10.1111/apa.14644 pmid: 30427066
49 L Chen, L Li, Y Han, B Lv, S Zou, Q Yu. 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
https://doi.org/10.1016/j.jphs.2020.02.009 pmid: 32173265
50 JA Fernández-Blanco, J Estévez, T Shea-Donohue, V Martínez, P Vergara. Changes in epithelial barrier function in response to parasitic infection: implications for IBD pathogenesis. J Crohn’s Colitis 2015; 9(6): 463–476
https://doi.org/10.1093/ecco-jcc/jjv056 pmid: 25820018
51 L Romani, F Del Chierico, M Chiriaco, S Foligno, S Reddel, G Salvatori, C Cifaldi, S Faraci, A Finocchi, P Rossi, P Bagolan, P D’Argenio, L Putignani, F Fusaro. 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
https://doi.org/10.3389/fcimb.2020.00059 pmid: 32158700
52 W Khoury-Hanold, B Yordy, P Kong, Y Kong, W Ge, K Szigeti-Buck, A Ralevski, TL Horvath, A Iwasaki. Viral spread to enteric neurons links genital HSV-1 infection to toxic megacolon and lethality. Cell Host Microbe 2016; 19(6): 788–799
https://doi.org/10.1016/j.chom.2016.05.008 pmid: 27281569
53 K Matsuda, CH Park, Y Sunden, T Kimura, K Ochiai, H Kida, T Umemura. The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice. Vet Pathol 2004; 41(2): 101–107
https://doi.org/10.1354/vp.41-2-101 pmid: 15017022
54 S Hosseini, E Wilk, K Michaelsen-Preusse, I Gerhauser, W Baumgärtner, R Geffers, K Schughart, M Korte. 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
https://doi.org/10.1523/JNEUROSCI.1740-17.2018 pmid: 29487124
55 JM Zhao, GD Zhou, YL Sun, SS Wang, JF Yang, EH Meng, D Pan, WS Li, XS Zhou, YD Wang, JY Lu, N Li, DW Wang, BC Zhou, TH Zhang. 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)
pmid: 15340561
56 Y Xiao, Q Meng, X Yin, Y Guan, Y Liu, C Li, M Wang, G Liu, T Tong, LF Wang, X Kong, D Wu. Pathological changes in masked palm civets experimentally infected by severe acute respiratory syndrome (SARS) coronavirus. J Comp Pathol 2008; 138(4): 171–179
https://doi.org/10.1016/j.jcpa.2007.12.005 pmid: 18343398
57 Y Yucel, N Gupta. Lymphatic drainage from the eye: a new target for therapy. Prog Brain Res 2015; 220: 185–198
https://doi.org/10.1016/bs.pbr.2015.07.028 pmid: 26497791
58 Z Zhang, JI Helman, LJ Li. 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
https://doi.org/10.4248/IJOS10006 pmid: 20690413
59 T Nedumpun, C Sirisereewan, C Thanmuan, P Techapongtada, R Puntarotairung, S Naraprasertkul, R Thanawongnuwech, S Suradhat. 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
https://doi.org/10.1016/j.vetmic.2018.01.014 pmid: 29519507
60 OA Khomich, SN Kochetkov, B Bartosch, AV Ivanov. Redox biology of respiratory viral infections. Viruses 2018; 10(8): E392
https://doi.org/10.3390/v10080392 pmid: 30049972
61 PB McCray Jr, L Pewe, C Wohlford-Lenane, M Hickey, L Manzel, L Shi, J Netland, HP Jia, C Halabi, CD Sigmund, DK Meyerholz, P Kirby, DC Look, S Perlman. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 2007; 81(2): 813–821
https://doi.org/10.1128/JVI.02012-06 pmid: 17079315
62 A Louveau, I Smirnov, TJ Keyes, JD Eccles, SJ Rouhani, JD Peske, NC Derecki, D Castle, JW Mandell, KS Lee, TH Harris, J Kipnis. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523(7560): 337–341
https://doi.org/10.1038/nature14432 pmid: 26030524
63 Y Cheng, J Haorah. How does the brain remove its waste metabolites from within? Int J Physiol Pathophysiol Pharmacol 2019; 11(6): 238–249
pmid: 31993098
64 MF Cashion, WA Banks, KL Bost, AJ Kastin. Transmission routes of HIV-1 gp120 from brain to lymphoid tissues. Brain Res 1999; 822(1-2): 26–33
https://doi.org/10.1016/S0006-8993(99)01069-0 pmid: 10082880
65 SV Dhuria, LR Hanson, WH Frey 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2010; 99(4): 1654–1673
https://doi.org/10.1002/jps.21924 pmid: 19877171
[1] Xiaoguang Xu, Wei Zhang, Mingquan Guo, Chenlu Xiao, Ziyu Fu, Shuting Yu, Lu Jiang, Shengyue Wang, Yun Ling, Feng Liu, Yun Tan, Saijuan Chen. Integrated analysis of gut microbiome and host immune responses in COVID-19[J]. Front. Med., 2022, 16(2): 263-275.
[2] Yi Zhang, Haocheng Zhang, Wenhong Zhang. SARS-CoV-2 variants, immune escape, and countermeasures[J]. Front. Med., 2022, 16(2): 196-207.
[3] Yiming Shao, Yingqi Wu, Yi Feng, Wenxin Xu, Feng Xiong, Xinxin Zhang. SARS-CoV-2 vaccine research and immunization strategies for improved control of the COVID-19 pandemic[J]. Front. Med., 2022, 16(2): 185-195.
[4] Wei Zhang, Xiaoguang Xu, Ziyu Fu, Jian Chen, Saijuan Chen, Yun Tan. PathogenTrack and Yeskit: tools for identifying intracellular pathogens from single-cell RNA-sequencing datasets as illustrated by application to COVID-19[J]. Front. Med., 2022, 16(2): 251-262.
[5] Zehong Huang, Yingying Su, Tianying Zhang, Ningshao Xia. A review of the safety and efficacy of current COVID-19 vaccines[J]. Front. Med., 2022, 16(1): 39-55.
[6] Yuntao Zhang, Yunkai Yang, Niu Qiao, Xuewei Wang, Ling Ding, Xiujuan Zhu, Yu Liang, Zibo Han, Feng Liu, Xinxin Zhang, Xiaoming Yang. Early assessment of the safety and immunogenicity of a third dose (booster) of COVID-19 immunization in Chinese adults[J]. Front. Med., 2022, 16(1): 93-101.
[7] Li Ni, Zheng Wen, Xiaowen Hu, Wei Tang, Haisheng Wang, Ling Zhou, Lujin Wu, Hong Wang, Chang Xu, Xizhen Xu, Zhichao Xiao, Zongzhe Li, Chene Li, Yujian Liu, Jialin Duan, Chen Chen, Dan Li, Runhua Zhang, Jinliang Li, Yongxiang Yi, Wei Huang, Yanyan Chen, Jianping Zhao, Jianping Zuo, Jianping Weng, Hualiang Jiang, Dao Wen Wang. Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial[J]. Front. Med., 2021, 15(5): 704-717.
[8] Long Chen, Bin Gu, Zhongpeng Wang, Lei Zhang, Minpeng Xu, Shuang Liu, Feng He, Dong Ming. EEG-controlled functional electrical stimulation rehabilitation for chronic stroke: system design and clinical application[J]. Front. Med., 2021, 15(5): 740-749.
[9] Rongtao Lai, Tianhui Zhou, Xiaogang Xiang, Jie Lu, Haiguang Xin, Qing Xie. Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections[J]. Front. Med., 2021, 15(4): 644-648.
[10] Dongsheng Wang, Binqing Fu, Zhen Peng, Dongliang Yang, Mingfeng Han, Min Li, Yun Yang, Tianjun Yang, Liangye Sun, Wei Li, Wei Shi, Xin Yao, Yan Ma, Fei Xu, Xiaojing Wang, Jun Chen, Daqing Xia, Yubei Sun, Lin Dong, Jumei Wang, Xiaoyu Zhu, Min Zhang, Yonggang Zhou, Aijun Pan, Xiaowen Hu, Xiaodong Mei, Haiming Wei, Xiaoling Xu. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial[J]. Front. Med., 2021, 15(3): 486-494.
[11] Guizhen Wang, Qun Zhao, Hui Zhang, Fan Liang, Chen Zhang, Jun Wang, Zhenyin Chen, Ran Wu, Hong Yu, Beibei Sun, Hua Guo, Ruie Feng, Kaifeng Xu, Guangbiao Zhou. Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells[J]. Front. Med., 2021, 15(2): 252-263.
[12] Junnan Liang, Guannan Jin, Tongtong Liu, Jingyuan Wen, Ganxun Li, Lin Chen, Wei Wang, Yuwei Wang, Wei Liao, Jia Song, Zeyang Ding, Xiao-ping Chen, Bixiang Zhang. Clinical characteristics and risk factors for mortality in cancer patients with COVID-19[J]. Front. Med., 2021, 15(2): 264-274.
[13] Baokai Dou, Shichun Li, Luyao Wei, Lixin Wang, Shiguo Zhu, Zhengtao Wang, Zunji Ke, Kaixian Chen, Zhifei Wang. Astragaloside IV suppresses post-ischemic natural killer cell infiltration and activation in the brain: involvement of histone deacetylase inhibition[J]. Front. Med., 2021, 15(1): 79-90.
[14] Yun Tan, Feng Liu, Xiaoguang Xu, Yun Ling, Weijin Huang, Zhaoqin Zhu, Mingquan Guo, Yixiao Lin, Ziyu Fu, Dongguo Liang, Tengfei Zhang, Jian Fan, Miao Xu, Hongzhou Lu, Saijuan Chen. Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection[J]. Front. Med., 2020, 14(6): 746-751.
[15] Siyi Li, Peilin Lv, Min He, Wenjing Zhang, Jieke Liu, Yao Gong, Ting Wang, Qiyong Gong, Yulin Ji, Su Lui. Cerebral regional and network characteristics in asthma patients: a resting-state fMRI study[J]. Front. Med., 2020, 14(6): 792-801.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed