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Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanisms

  • Abdul Mannan Baig*
    Abdul Mannan Baig
    Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
    *Tel: +92-(0)333-2644-246. E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0003-0626-216X
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  • Areeba Khaleeq
    Areeba Khaleeq
    Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
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    • , 
  • Usman Ali
    Usman Ali
    Medical College, Aga Khan University, Karachi 74800, Pakistan
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    • , and 
  • Hira Syeda
    Hira Syeda
    Department of Biosciences, Mohammad Ali Jinnah University, Karachi 75400, Pakistan
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Cite this: ACS Chem. Neurosci. 2020, 11, 7, 995–998
Publication Date (Web):March 13, 2020
https://doi.org/10.1021/acschemneuro.0c00122
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Abstract

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The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and has evoked a scare of epic proportion regarding its potential to spread and infect humans worldwide. As we are in the midst of an ongoing pandemic of COVID-19, scientists are struggling to understand how it resembles and differs from the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreak, it has been shown that, similar to SARS-CoV, COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurological tissue and determining the possible contribution of neurological tissue damage to the morbidity and mortality caused by COIVD-19. Here, we investigate the density of the expression levels of ACE2 in the CNS, the host–virus interaction and relate it to the pathogenesis and complications seen in the recent cases resulting from the COVID-19 outbreak. Also, we debate the need for a model for staging COVID-19 based on neurological tissue involvement.

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  Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

1. The Novel COVID-19 Virus

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The first reports of the viral infection attracted attention in late December 2019 in Wuhan, the capital of Hubei, China. Later, it was revealed that the virus responsible for causing the infections was contagious between humans. By early January, terms like “the new coronavirus” and “Wuhan coronavirus” were in common use. On February 11, 2020, a taxonomic designation “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) became the official means to refer to the virus strain, that was previously termed as 2019-nCoV and Wuhan coronavirus. Within a few hours on the same day, the WHO officially renamed the disease as COVID-19.

2. The Genome of the COVID-19 Virus

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The complete genome of SARS-CoV-2 from Wuhan, China was submitted on January 17, 2020 in the National Center for Biotechnology(1) (NCBI) database, with ID NC_045512. The genome of SARS-CoV-2 is a 29,903 bp single-stranded RNA (ss-RNA) coronavirus. It has now been shown that the virus causing COVID-19 is a SARS-like coronavirus that had previously been reported in bats in China.

3. Tissue Distribution of ACE2 in Human Organs and Tissues

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In order to discover the neurovirulence of SARS-CoV-2 and relate it to neurological tissue expression of ACE2, data retrieval was done from human protein databases. Most of the evidence of ACE2 expression in the brain (Figure 1) comes from literature and mammalian tissue expression databases,(2) which prompted us to investigate neurotropic effects of SARS-CoV-2 and its contribution toward the morbidity and mortality of patients with COVID-19.

Figure 1

Figure 1. Tissue distribution of ACE2 receptors in humans. Viremia (A) disseminates the COVID-19 virus throughout the body via the bloodstream (B). Neurotropism may occur via circulation and/or an upper nasal trancribrial route that enables the COVID-19 to reach the brain (C) and bind and engage with the ACE2 receptors (D, blue). COVID-19 docks on the ACE2 via spike protein (D, golden spikes). Shown are lungs, heart, kidneys, intestines, brain, and testicles that are well-known to express ACE2 receptors and are possible targets of COVID-19.

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3.1. Evidence of the Distribution of ACE2 in the Human Brain

The brain has been reported to express ACE2 receptors (Figure 1A, C) that have been detected over glial cells and neurons, which makes them a potential target of COVID-19. Previous studies have shown the ability of SARS-CoV to cause neuronal death in mice by invading the brain via the nose close to the olfactory epithelium.(3) The contribution of the neurotropic potential of SARS-CoV-2 in patients reported in the recent outbreak of COVID-19 remains to be established. In the SARS-CoV infections that were reported in the past, autopsy findings of the patients have shown strong evidence of the presence of SARS-CoV by electron microscopy, immunohistochemistry, and real-time reverse transcription-PCR (3). Patients with acute SARS-CoV illness have also demonstrated the presence of the virus in cerebrospinal fluid. The role of the blood-brain barrier in containing the virus and preventing it from gaining access to the neural tissues needs to be further explored in patients diagnosed with COVID-19. Recently, a study posted in medRxiv(4) has reported neurological manifestations in COVID-19 in the current outbreak that involved 214 patients, of which 78 (36.4%) patients had neurologic manifestations, which affirms our rationale of the neurotropic potential in the COVID-19 virus. Also, a finding published on a patient who had loss of involuntary control over breathing(5) during the recent outbreak with several other patients suffering acute respiratory failure implores healthcare professionals and clinicians to segregate COVID-19 patients into neurologically affected cases and those who are devoid of neurological deficits.

4. Host–Virus Interaction: How the ACE2 Receptor Is Exploited by the COVID-19 Virus to Gain Entry Inside the Host Cells

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With the mRNA encoding several other proteins,(1) the COVID-19 virus, like SARS-CoV, uses a spike protein S1 that enables the attachment of the virion to the cell membrane by interacting with host ACE2 receptor(3,6) (Figure 1C, D). In the later study,(6) it was shown that the ACE2 binding affinity of the 2019-nCoV spike protein ectodomain was 10–20-fold higher than that of the SARS-CoV spike protein. A BLASTp search of the COVID-19 virus (SARS-CoV-2) receptor binding domain (RBD) subdomain-1 (319th to 591st aa) fetched a spike glycoprotein [bat coronavirus RaTG13] and S1 protein partial [SARS coronavirus GD322] as homologs. Pairwise sequence alignments of the three sequences show that although the spike proteins of all three CoV are highly similar they are not identical (Figure 2A, horizontal arrows), which may be the reason for the higher binding affinity of the COVID-19 spike protein to the human ACE2 receptor. Homology modeling of SARS-CoV-2 RBD subdomain-1 (319th to 591st aa) in the SWISS-MODEL automated server developed a template-based model of the SARS-CoV-2 spike glycoprotein with a single receptor-binding domain in the up configuration (Figure 2A1) with 100% sequence identity. Of the other template-based models developed, it expectedly showed a model of the structure of the SARS-CoV spike glycoprotein, conformation 2 with about 74% sequence identity (Figure 2B, B1), which shows them to be structurally and evolutionarily related.

Figure 2

Figure 2. (A) Sequence alignment of COVID-19 RBD subdomain-1 (319th to 591st) amino acid (top row) with the bat and SARS-CoV spike protein (middle and bottom row) that were fetched from BLASTp results of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acids. Note horizontal arrows that show areas of contrast between the sequences. (A1) Homology modeling of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acid developed a template (6vsb.1. A)-based model of the COVID-19 virus spike glycoprotein. (B). Homology modeling of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acid developed a template-(5x5b.1.A) based model of the prefusion structure of SARS-CoV spike glycoprotein in conformation 2 (B1) with 73.96% sequence identity. [Uniprot and SWISS-MODEL automated server were used for sequence alignments and development of the templates and models, respectively.]

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5. A Proposed Cascade of Cerebral Involvement in the COVID-19 Infections

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The dissemination of COVID-19 in the systemic circulation or across the cribriform plate of the ethmoid bone (Figure 1) during an early or later phase of the infection can lead to cerebral involvement as has been reported in the past for SARS-CoV affected patients.(3) The presence of the COVID-19 virus in the general circulation understandably enables it to pass into the cerebral circulation (Figure 1A–C) where the sluggish movement of the blood within the microcirculation could be one of the factors that may facilitate the interaction of the COVID-19 virus spike protein with ACE2 expressed in the capillary endothelium. Subsequent budding of the viral particles from the capillary endothelium and damage to the endothelial lining can favor viral access to the brain (Figure 1B). Once within the milieu of the neuronal tissues, its interaction with ACE2 receptors (Figure 1C, D) expressed in neurons(2) can initiate a cycle of viral budding accompanied by neuronal damage without substantial inflammation as has been seen with cases of SARS-CoV(3) in the past. It is important to mention here that, long before the proposed anticipated neuronal damages occur, the endothelial ruptures in cerebral capillaries accompanied by bleeding within the cerebral tissue can have fatal consequences in patients with COVID-19 infections. The movement of the COVID-19 virus to the brain via the cribriform plate close to the olfactory bulb can be an additional pathway that could enable the virus to reach and affect the brain. Additionally, the findings like an altered sense of smell or hyposmia in an uncomplicated early stage COVID-19 patient should be investigated thoroughly for CNS involvement.

6. Conclusions and Future Directions

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Autopsies of the COVID-19 patients, detailed neurological investigation, and attempts to isolate SARS-CoV-2 from the endothelium of cerebral microcirculation, cerebrospinal fluid, glial cells, and neuronal tissue can clarify the role played by this novel COVID-19 causing coronavirus in the ongoing mortalities as has been in the recent outbreak. It is important to mention here that although the cerebral damage may complicate a COVID-19 infection, it appears that it is the widespread dysregulation of homeostasis caused by pulmonary, renal, cardiac, and circulatory damage that proves fatal in COIVD-19 patients. With that being said, a dominant cerebral involvement alone with the potential of causing cerebral edema in COVID-19 can take a lead in causing death long before systemic homeostatic dysregulation sets in. Access of the COVID-19 virus to the brain via the transcribrial route, as described previously for other CNS targeting pathogens,(7) could have been the case in a recently reported patient with hyposmia and the cases of acute respiratory failure in COVID-19,(5) which needs to be further elucidated by isolating the SARS-CoV-2 virus from the zones that are in proximity to the olfactory bulb. It is expected that the differences in the sequence of spike proteins between COVID-19 virus and SARS-CoV (Figure 2A) will enable scientists to identify epitopes in COVID-19 virus for the development of monoclonal antibodies against this virus. With the recent COVID-19 outbreak, there is an urgent need to understand the neurotropic potential of the COVID-19 virus in order to prioritize and individualize the treatment protocols based on the severity of the disease and predominant organ involvement. Also, a staging system based on the severity and organ involvement is needed in COVID-19 in order to rank the patients for aggressive or conventional treatment modalities.

This project was partly funded by Aga Khan University.

The authors declare no competing financial interest.

Notes

The terms COVID-19 virus and SARS-CoV-2 are used in this paper, that refer to the novel coronavirus involved in the ongoing outbreak.

Author Information

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  • Corresponding Author
  • Authors
    • Areeba Khaleeq - Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan
    • Usman Ali - Medical College, Aga Khan University, Karachi 74800, Pakistan
    • Hira Syeda - Department of Biosciences, Mohammad Ali Jinnah University, Karachi 75400, Pakistan
  • Funding

    This project was partly funded by Aga Khan University.

  • Notes

    The authors declare no competing financial interest.

Acknowledgments

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The authors would like to thank the staff and faculty members of the Department of Biological & Biomedical Sciences, Aga Khan University, who, despite their busy schedule, made it to the COVID-19 presentations made by the authors and provided them with their input on the rationale of this study. The authors would also like to acknowledge the efforts of Ms. Preet Katyara for her critical review of our paper.

References

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This article references 7 other publications.

  1. 1
    Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, complete genome. Nucleotide, National Center for Biotechnology Information (NCBI), National Library of Medicine (US), National Center for Biotechnology Information, Bethesda, MD, https://www.ncbi.nlm.nih.gov/nuccore/1798174254 (accessed on 2020-02-28).
    Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Palasca, O., Santos, A., Stolte, C., Gorodkin, J., and Jensen, L. J. (2018) TISSUES 2.0: an integrative web resource on mammalian tissue expression. Database 2018, bay003  DOI: 10.1093/database/bay003
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82 (15), 7264– 75,  DOI: 10.1128/JVI.00737-08
    [Crossref], [PubMed], [CAS], Google Scholar
    3
    Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2
    Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, Stanley
    Journal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovVSltr4%253D&md5=b5d85df75cb9f2ab540c952704ff5377
  4. 4
    Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Li, Y., Jin, H., and Hu, B. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv, 2020.02.22.20026500 DOI: 10.1101/2020.02.22.20026500 (accessed on 2020-02-28).
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  5. 5
    Li, Y. C., Bai, W. Z., and Hashikawa, T. (2020) The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients. J. Med. Virol.  DOI: 10.1002/jmv.25728
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., Graham, B. S., and McLellan, J. S. (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science eabb2507  DOI: 10.1126/science.abb2507
    [Crossref], [PubMed], Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Baig, A. M. (2016) Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chem. Neurosci. 7 (8), 1026– 9,  DOI: 10.1021/acschemneuro.6b00197
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    7
    Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri
    Baig, Abdul Mannan
    ACS Chemical Neuroscience (2016), 7 (8), 1026-1029CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    A review. Naegleria fowleri causes one of the most devastating necrotic meningoencephalitis in humans. The infection caused by this free-living amoeba is universally fatal within a week of onset of the signs and symptoms of the disease called primary amoebic meningoencephalitis (PAM). In all the affected patients, there is always a history of entry of water into the nose. Even though the diagnostic and treatment protocols have been revised and improved, the obstinate nature of the disease can be gauged by the fact that the mortality rate has persisted around ∼95% over the past 60 years. Some of the unanswered questions regarding PAM are is there a neurochem. basis of the chemotaxis of N. fowleri to the brain. What immune evasion means occurs preceding the neurotropic invasion. What is the contribution of the acute inflammatory response in the fatal cases. Can a combination of antiamoebic drugs with antagonism of the acute inflammation help save the patient's life. As prevention remains the most valuable safeguard against N. fowleri, a quicker diagnosis, better understanding of the pathogenesis of PAM coupled with testing of newer and safer drugs could improve the chances of survival in patients affected with PAM.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2lsb7I&md5=715fbdb82bc345f03c187d02ded6e057

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  31. Serhiy Souchelnytskyi, Andriy Nera, Nazariy Souchelnytskyi. COVID-19 engages clinical markers for the management of cancer and cancer-relevant regulators of cell proliferation, death, migration, and immune response. Scientific Reports 2021, 11 (1) https://doi.org/10.1038/s41598-021-84780-y
  32. Mohamud Sheek-Hussein, Fikri M. Abu-Zidan, Emmanuel Stip. Disaster management of the psychological impact of the COVID-19 pandemic. International Journal of Emergency Medicine 2021, 14 (1) https://doi.org/10.1186/s12245-021-00342-z
  33. Michael T. Lawton, Ehsan Alimohammadi, Seyed Reza Bagheri, Arash Bostani, Siavash Vaziri, Ali Karbasforoushan, Kossar Mozaffari, Mehran Bahrami Bukani, Alireza Abdi. Coronavirus disease 2019 (COVID-19) can predispose young to Intracerebral hemorrhage: a retrospective observational study. BMC Neurology 2021, 21 (1) https://doi.org/10.1186/s12883-021-02109-8
  34. Matthew Cadd, Maya Nunn. An A-E assessment of post-ICU COVID-19 recovery. Journal of Intensive Care 2021, 9 (1) https://doi.org/10.1186/s40560-021-00544-w
  35. Ghadha Ibrahim Fouad. The neuropathological impact of COVID-19: a review. Bulletin of the National Research Centre 2021, 45 (1) https://doi.org/10.1186/s42269-020-00478-7
  36. Meenesh Juvekar, Baisali Sarkar. Guidelines for otorhinolaryngologists and head neck surgeons in coronavirus disease 2019 pandemic. The Egyptian Journal of Otolaryngology 2021, 37 (1) https://doi.org/10.1186/s43163-021-00082-0
  37. Xiaohuan Xia, Yi Wang, Jialin Zheng. COVID-19 and Alzheimer’s disease: how one crisis worsens the other. Translational Neurodegeneration 2021, 10 (1) https://doi.org/10.1186/s40035-021-00237-2
  38. Juan I. Guerrero, Luis A. Barragán, Juan D. Martínez, Juan P. Montoya, Alejandra Peña, Fidel E. Sobrino, Zulma Tovar-Spinoza, Kemel A. Ghotme. Central and peripheral nervous system involvement by COVID-19: a systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings. BMC Infectious Diseases 2021, 21 (1) https://doi.org/10.1186/s12879-021-06185-6
  39. Baila Shakaib, Tanzeel Zohra, Aamer Ikram, Muhammad Bin Shakaib, Amna Ali, Adnan Bashir, Muhammad Salman, Mumtaz Ali khan, Jamil Ansari. A comprehensive review on clinical and mechanistic pathophysiological aspects of COVID-19 Malady: How far have we come?. Virology Journal 2021, 18 (1) https://doi.org/10.1186/s12985-021-01578-0
  40. Alexander Kusnik, Christel Weiss, Melanie Neubauer, Bianca Huber, Marlis Gerigk, Thomas Miethke, Nicole Hunter, Nicole Rotter, Sonja Ludwig, Angela Schell, Matthias P. Ebert, Andreas Teufel. Presence of gustatory and olfactory dysfunction in the time of the COVID-19 pandemic. BMC Infectious Diseases 2021, 21 (1) https://doi.org/10.1186/s12879-021-06294-2
  41. HariOm Singh, Amita Singh, Abdul Arif Khan, Vivek Gupta. Immune mediating molecules and pathogenesis of COVID-19-associated neurological disease. Microbial Pathogenesis 2021, 158 , 105023. https://doi.org/10.1016/j.micpath.2021.105023
  42. Kiarash Saleki, Shakila Yaribash, Mohammad Banazadeh, Ehsan Hajihosseinlou, Mahdi Gouravani, Amene Saghazadeh, Nima Rezaei. Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies. European Journal of Pharmacology 2021, 906 , 174248. https://doi.org/10.1016/j.ejphar.2021.174248
  43. Jie Gao, Li Zeng, Linlin Yao, Ziniu Wang, Xiaoxi Yang, Jianbo Shi, Ligang Hu, Qian Liu, Chunying Chen, Tian Xia, Guangbo Qu, Xian-En Zhang, Guibin Jiang. Inherited and acquired corona of coronavirus in the host: Inspiration from the biomolecular corona of nanoparticles. Nano Today 2021, 39 , 101161. https://doi.org/10.1016/j.nantod.2021.101161
  44. Deepak Mishra, Radha Raman Maurya, Kamlesh Kumar, Nupur S. Munjal, Vijay Bahadur, Sandeep Sharma, Prashant Singh, Indra Bahadur. Structurally modified compounds of hydroxychloroquine, remdesivir and tetrahydrocannabinol against main protease of SARS-CoV-2, a possible hope for COVID-19: Docking and molecular dynamics simulation studies. Journal of Molecular Liquids 2021, 335 , 116185. https://doi.org/10.1016/j.molliq.2021.116185
  45. Isabella Canavero, Sabrina Ravaglia, Francesca Valentino, Giuseppe Micieli. Guillain Barrè syndrome and myelitis associated with SARS-CoV-2 infection. Neuroscience Letters 2021, 759 , 136040. https://doi.org/10.1016/j.neulet.2021.136040
  46. Valerie Jeanneret, Daniel Winkel, Aida Risman, Hang Shi, Grace Gombolay. Post-infectious rhombencephalitis after coronavirus-19 infection: A case report and literature review. Journal of Neuroimmunology 2021, 357 , 577623. https://doi.org/10.1016/j.jneuroim.2021.577623
  47. Akbar Hasanzadeh, Masoomeh Alamdaran, Sepideh Ahmadi, Helena Nourizadeh, Mohammad Aref Bagherzadeh, Mirza Ali Mofazzal Jahromi, Perikles Simon, Mahdi Karimi, Michael R. Hamblin. Nanotechnology against COVID-19: Immunization, diagnostic and therapeutic studies. Journal of Controlled Release 2021, 336 , 354-374. https://doi.org/10.1016/j.jconrel.2021.06.036
  48. Mohammad Mahdi Nejadi Babadaei, Anwarul Hasan, Samir Haj Bloukh, Zehra Edis, Majid Sharifi, Ehsan Kachooei, Mojtaba Falahati. The expression level of angiotensin-converting enzyme 2 determines the severity of COVID-19: lung and heart tissue as targets. Journal of Biomolecular Structure and Dynamics 2021, 39 (10) , 3780-3786. https://doi.org/10.1080/07391102.2020.1767211
  49. Jiali Xu, Zifeng Wu, Mi Zhang, Shijiang Liu, Ling Zhou, Chun Yang, Cunming Liu. The Role of the Gastrointestinal System in Neuroinvasion by SARS-CoV-2. Frontiers in Neuroscience 2021, 15 https://doi.org/10.3389/fnins.2021.694446
  50. Katelynn Ondek, Aida Nasirishargh, Jacquelyn R. Dayton, Miriam A. Nuño, Lillian Cruz-Orengo. Strain and sex differences in somatosensation and sociability during experimental autoimmune encephalomyelitis. Brain, Behavior, & Immunity - Health 2021, 14 , 100262. https://doi.org/10.1016/j.bbih.2021.100262
  51. Diego Cardoso Fragoso, Catherine Marx, Bruna Garbugio Dutra, Carlos Jorge da Silva, Pollyanna Martins da Silva, Antônio Carlos Martins Maia Junior, Mariana Crema Tobara, Camila de Almeida Silva, Livio Dias, Angela Cristina Polycarpo, Rosana Richtmann. COVID-19 as a Cause of Acute Neonatal Encephalitis and Cerebral Cytotoxic Edema. Pediatric Infectious Disease Journal 2021, 40 (7) , e270-e271. https://doi.org/10.1097/INF.0000000000003145
  52. Yuce Islamoglu, Burak Celik, Muzaffer Kiris. Facial paralysis as the only symptom of COVID-19: A prospective study. American Journal of Otolaryngology 2021, 42 (4) , 102956. https://doi.org/10.1016/j.amjoto.2021.102956
  53. Susan M. Burks, Hector Rosas-Hernandez, Manuel Alejandro Ramirez-Lee, Elvis Cuevas, John C. Talpos. Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier?. Brain, Behavior, and Immunity 2021, 95 , 7-14. https://doi.org/10.1016/j.bbi.2020.12.031
  54. Leila Alba, Cristina Coll, Sonia Sáez, Lucía Alonso, Helena Pérez, Saray Palma, Virginia Vallés, Sonia Ortiz. New-onset psychosis: A case report of brief psychosis related to COVID-19 infection. Psychiatry Research 2021, 301 , 113975. https://doi.org/10.1016/j.psychres.2021.113975
  55. Marta Waliszewska-Prosół, Sławomir Budrewicz. The unusual course of a migraine attack during COVID-19 infection — Case studies of three patients. Journal of Infection and Public Health 2021, 14 (7) , 903-905. https://doi.org/10.1016/j.jiph.2021.04.013
  56. Oxana Semyachkina-Glushkovskaya, Aysel Mamedova, Valeria Vinnik, Maria Klimova, Elena Saranceva, Vasily Ageev, Tingting Yu, Dan Zhu, Thomas Penzel, Jürgen Kurths. Brain Mechanisms of COVID-19-Sleep Disorders. International Journal of Molecular Sciences 2021, 22 (13) , 6917. https://doi.org/10.3390/ijms22136917
  57. Ali Afshar-Oromieh, Helmut Prosch, Cornelia Schaefer-Prokop, Karl Peter Bohn, Ian Alberts, Clemens Mingels, Majda Thurnher, Paul Cumming, Kuangyu Shi, Alan Peters, Silvana Geleff, Xiaoli Lan, Feng Wang, Adrian Huber, Christoph Gräni, Johannes T. Heverhagen, Axel Rominger, Matthias Fontanellaz, Heiko Schöder, Andreas Christe, Stavroula Mougiakakou, Lukas Ebner. A comprehensive review of imaging findings in COVID-19 - status in early 2021. European Journal of Nuclear Medicine and Molecular Imaging 2021, 48 (8) , 2500-2524. https://doi.org/10.1007/s00259-021-05375-3
  58. Sérgio Brasil, Fabio Silvio Taccone, Sâmia Yasin Wahys, Bruno Martins Tomazini, Filippo Annoni, Sérgio Fonseca, Estevão Bassi, Bruno Lucena, Ricardo De Carvalho Nogueira, Marcelo De-Lima-Oliveira, Edson Bor-Seng-Shu, Wellingson Paiva, Alexis Fournier Turgeon, Manoel Jacobsen Teixeira, Luiz Marcelo Sá Malbouisson. Cerebral Hemodynamics and Intracranial Compliance Impairment in Critically Ill COVID-19 Patients: A Pilot Study. Brain Sciences 2021, 11 (7) , 874. https://doi.org/10.3390/brainsci11070874
  59. Sawrab Roy, Binayok Sharma, Md. Ishtiaque Mazid, Rubaiat Nazneen Akhand, Moumita Das, Marufatuzzahan Marufatuzzahan, Tanjia Afrin Chowdhury, Kazi Faizul Azim, Mahmudul Hasan. Identification and host response interaction study of SARS-CoV-2 encoded miRNA-like sequences: an in silico approach. Computers in Biology and Medicine 2021, 134 , 104451. https://doi.org/10.1016/j.compbiomed.2021.104451
  60. Carmela Conte. Possible Link between SARS-CoV-2 Infection and Parkinson’s Disease: The Role of Toll-Like Receptor 4. International Journal of Molecular Sciences 2021, 22 (13) , 7135. https://doi.org/10.3390/ijms22137135
  61. Zeba Firdaus, Sushil Kumar Singh, Tryambak Deo Singh, Meenakshi Singh. The scientific community in COVID-19 global pandemic: A systematic update on recent progress and challenges. European Journal of Chemistry 2021, 12 (2) , 222-234. https://doi.org/10.5155/eurjchem.12.2.222-234.2084
  62. Kerem Kökoğlu, Nezaket Tektaş, Fidan Elif Baktir-Okcesiz, Mehmet İlhan Şahin. Mild and moderate COVID-19 disease does not affect hearing function permanently: a cross-sectional study ınvolving young and middle-aged healthcare givers. European Archives of Oto-Rhino-Laryngology 2021, 27 https://doi.org/10.1007/s00405-021-06883-6
  63. Ibrahim Aminu Shehu, Nura Mustapha Auwal, Muhammad Kabir Musa, Abubakar Mukhtar, Mashahudu Sha’arani Yusuf, Anees Ashir Yau, Murtala Muhammad, Yusuf Baba Dala, Salisu Abdullahi Sani, Mahmoud Seed Ahmad, Mojahidul Islam. Innovative Nanotechnology a Boon for Fight Against Pandemic COVID–19. Frontiers in Nanotechnology 2021, 3 https://doi.org/10.3389/fnano.2021.651308
  64. Che Mohd Nasril Che Mohd Nassir, Sabarisah Hashim, Kah Keng Wong, Sanihah Abdul Halim, Nur Suhaila Idris, Nanthini Jayabalan, Dazhi Guo, Muzaimi Mustapha. COVID-19 Infection and Circulating Microparticles—Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease. Molecular Neurobiology 2021, 33 https://doi.org/10.1007/s12035-021-02457-z
  65. Helia Jafari Khaljiri, Monire Jamalkhah, Ali Amini Harandi, Hossein Pakdaman, Milad Moradi, Ashkan Mowla. Comprehensive Review on Neuro-COVID-19 Pathophysiology and Clinical Consequences. Neurotoxicity Research 2021, 277 https://doi.org/10.1007/s12640-021-00389-z
  66. Eman M. Khedr, Ahmed Shoyb, Khaled O. Mohamed, Ahmed A. Karim, Mostafa Saber. Case Report: Guillain–Barré Syndrome Associated With COVID-19. Frontiers in Neurology 2021, 12 https://doi.org/10.3389/fneur.2021.678136
  67. Lei Tang, Shixin Liu, Yanhe Xiao, Thi My Linh Tran, Ji Whae Choi, Jing Wu, Kasey Halsey, Raymond Y. Huang, Jerrold Boxerman, Sohil H Patel, David Kung, Renyu Liu, Michael D. Feldman, Daniel D Danoski, Wei‐hua Liao, Scott E. Kasner, Tao Liu, Bo Xiao, Paul J. Zhang, Michael Reznik, Harrison X. Bai, Li Yang. Encephalopathy at admission predicts adverse outcomes in patients with SARS‐CoV‐2 infection. CNS Neuroscience & Therapeutics 2021, 29 https://doi.org/10.1111/cns.13687
  68. Shah T Sarmast, Alaa S Mohamed, Zain Amar, Sobia Sarwar, Zahoor Ahmed. A Case of Acute Encephalitis in COVID-19 Patient: A Rare Complication. Cureus 2021, 323 https://doi.org/10.7759/cureus.15636
  69. Ravinder K. Kaundal, Anil K. Kalvala, Ashutosh Kumar. Neurological Implications of COVID-19: Role of Redox Imbalance and Mitochondrial Dysfunction. Molecular Neurobiology 2021, 172 https://doi.org/10.1007/s12035-021-02412-y
  70. Moaaz Baghal, Mohamed Ahmed, Mounir Ibrahim, Syed Jafri, Sameh Elias. An Unusual Case of Acute Hemorrhagic Necrotizing Encephalomyelitis in a COVID-19 Patient. Cureus 2021, 2015 https://doi.org/10.7759/cureus.15542
  71. Debasis Behera, Ruchi Rekha Behera, Suman Kumar Jagaty, Rekha Das, Rajesh Venkataram, Saswat Subhankar, Vikram Samal. An Atypical Case of Mild COVID-19 Infection with Severe Guillain-Barré Syndrome as Neurological Manifestation. Journal of Health and Allied Sciences NU 2021, 5 https://doi.org/10.1055/s-0041-1731142
  72. Rabia Bouali‐Benazzouz, Abdelhamid Benazzouz. Covid‐19 Infection and Parkinsonism: Is There a Link?. Movement Disorders 2021, 13 https://doi.org/10.1002/mds.28680
  73. Paolo Manganotti, Giulia Bellavita, Valentina Tommasini, Laura D′Acunto, Martina Fabris, Laura Cecotti, Giovanni Furlanis, Arianna Sartori, Lucia Bonzi, Alex Buoite Stella, Valentina Pesavento. Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID‐19 neuropathy patients. Journal of Medical Virology 2021, 77 https://doi.org/10.1002/jmv.27061
  74. Medha Karnik, Narasimha M. Beeraka, Chinnappa A. Uthaiah, Suma M. Nataraj, Anjali Devi S. Bettadapura, Gjumrakch Aliev, SubbaRao V. Madhunapantula. A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development. Molecular Neurobiology 2021, 9 https://doi.org/10.1007/s12035-021-02399-6
  75. Masoomeh Dadkhah, Sahand Talei, Donya Doostkamel, Soheila Molaei, Nima Rezaei. The impact of COVID-19 on diagnostic biomarkers in neuropsychiatric and neuroimmunological diseases: a review. Reviews in the Neurosciences 2021, Article ASAP.
  76. Adriano José Maia Chaves Filho, Franciane Gonçalves, Melina Mottin, Carolina Horta Andrade, Silvia Nunes Szente Fonseca, Danielle S. Macedo. Repurposing of Tetracyclines for COVID-19 Neurological and Neuropsychiatric Manifestations: A Valid Option to Control SARS-CoV-2-Associated Neuroinflammation?. Journal of Neuroimmune Pharmacology 2021, 16 (2) , 213-218. https://doi.org/10.1007/s11481-021-09986-3
  77. Bingfeng Zheng, Manman Yuan, Qinhai Ma, Shenglan Wang, Yang Tan, Yizhu Xu, Jing Ye, Yanjie Gao, Xueqing Sun, Zifeng Yang, Peipei Xu, Lingdong Kong, Xingxin Wu, Qiang Xu. Landscape of SARS-CoV-2 spike protein-interacting cells in human tissues. International Immunopharmacology 2021, 95 , 107567. https://doi.org/10.1016/j.intimp.2021.107567
  78. Maryam Bayat, Yahya Asemani, Mohammad Reza Mohammadi, Mahsa Sanaei, Mozhdeh Namvarpour, Reyhaneh Eftekhari. An overview of some potential immunotherapeutic options against COVID-19. International Immunopharmacology 2021, 95 , 107516. https://doi.org/10.1016/j.intimp.2021.107516
  79. Preeti Joshi, R K Tyagi, Krishna Mohan Agarwal. Technological Resources for Fighting COVID-19 Pandemic Health Issues. Journal of Industrial Integration and Management 2021, 06 (02) , 271-285. https://doi.org/10.1142/S2424862221500196
  80. Sofía Lallana, Austin Chen, Manuel Requena, Marta Rubiera, Anna Sanchez, James E. Siegler, Marián Muchada. Posterior reversible encephalopathy syndrome (PRES) associated with COVID-19. Journal of Clinical Neuroscience 2021, 88 , 108-112. https://doi.org/10.1016/j.jocn.2021.03.028
  81. Mohan Kumar Muthu Karuppan, Dinesh Devadoss, Madhavan Nair, Hitendra S. Chand, Madepalli K. Lakshmana. SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism. Molecular Neurobiology 2021, 58 (6) , 2465-2480. https://doi.org/10.1007/s12035-020-02245-1
  82. Philip W. Rouadi, Samar A. Idriss, Jean Bousquet. Olfactory and taste dysfunctions in COVID-19. Current Opinion in Allergy & Clinical Immunology 2021, 21 (3) , 229-244. https://doi.org/10.1097/ACI.0000000000000735
  83. Finja Schweitzer, Nina N. Kleineberg, Yasemin Göreci, Oezguer A. Onur, Christiana Franke, Clemens Warnke. Neuro-COVID-19 is more than anosmia: clinical presentation, neurodiagnostics, therapies, and prognosis. Current Opinion in Neurology 2021, 34 (3) , 423-431. https://doi.org/10.1097/WCO.0000000000000930
  84. Ljiljana Marcic, Marino Marcic, Sanja Lovric Kojundzic, Barbara Marcic, Vesna Capkun, Katarina Vukojevic. Personalized Approach to Patient with MRI Brain Changes after SARS-CoV-2 Infection. Journal of Personalized Medicine 2021, 11 (6) , 442. https://doi.org/10.3390/jpm11060442
  85. Vincenzo Lionetti, Sveva Bollini, Raffaele Coppini, Andrea Gerbino, Alessandra Ghigo, Guido Iaccarino, Rosalinda Madonna, Fabio Mangiacapra, Michele Miragoli, Francesco Moccia, Luca Munaron, Pasquale Pagliaro, Astrid Parenti, Teresa Pasqua, Claudia Penna, Federico Quaini, Carmine Rocca, Michele Samaja, Laura Sartiani, Teresa Soda, Carlo Gabriele Tocchetti, Tommaso Angelone. Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development. Pharmacological Research 2021, 168 , 105581. https://doi.org/10.1016/j.phrs.2021.105581
  86. Hamidreza Mortazavy Beni, Hamed mortazavi, Fatemeh Aghaei, Sanam Kamalipour. Experimental tracking and numerical mapping of novel coronavirus micro-droplet deposition through nasal inhalation in the human respiratory system. Biomechanics and Modeling in Mechanobiology 2021, 20 (3) , 1087-1100. https://doi.org/10.1007/s10237-021-01434-8
  87. Keith J. Kincaid, Justin C. Kung, Alexander J. Senetar, David Mendoza, Daniel A. Bonnin, Windy L. Purtlebaugh, Rainier M. Cabatbat, Rondalyn Dickens, Franklin D. Echevarria, Vidhu Kariyawasam, Maria Bruzzone, Alexis N. Simpkins. Post-COVID seizure: A new feature of “long-COVID”. eNeurologicalSci 2021, 23 , 100340. https://doi.org/10.1016/j.ensci.2021.100340
  88. Sutapa Som Chaudhury, Koel Sinha, Rabindranath Majumder, Atanu Biswas, Chitrangada Das Mukhopadhyay. COVID-19 and central nervous system interplay: A big picture beyond clinical manifestation. Journal of Biosciences 2021, 46 (2) https://doi.org/10.1007/s12038-021-00165-3
  89. Don A. Davies, Aida Adlimoghaddam, Benedict C. Albensi. The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease. Molecular Neurobiology 2021, 579 https://doi.org/10.1007/s12035-021-02438-2
  90. Violaine Piquet, Cédric Luczak, Fabien Seiler, Jordan Monaury, Alexandre Martini, Anthony B. Ward, Jean-Michel Gracies, Damien Motavasseli, Violaine Piquet, Cédric Luczak, Fabien Seiler, Jordan Monaury, Estelle Lépine, Lucile Chambard, Marjolaine Baude, Emilie Hutin, Alexandre Martini, Andrés Samaniego, Nicolas Bayle, Anthony B. Ward, Jean-Michel Gracies, Damien Motavasseli. Do Patients With COVID-19 Benefit from Rehabilitation? Functional Outcomes of the First 100 Patients in a COVID-19 Rehabilitation Unit. Archives of Physical Medicine and Rehabilitation 2021, 102 (6) , 1067-1074. https://doi.org/10.1016/j.apmr.2021.01.069
  91. Maryline Santerre, Sterling P. Arjona, Charles NS Allen, Natalia Shcherbik, Bassel E. Sawaya. Why do SARS-CoV-2 NSPs rush to the ER?. Journal of Neurology 2021, 268 (6) , 2013-2022. https://doi.org/10.1007/s00415-020-10197-8
  92. Madhu Jasti, Krishna Nalleballe, Vasuki Dandu, Sanjeeva Onteddu. A review of pathophysiology and neuropsychiatric manifestations of COVID-19. Journal of Neurology 2021, 268 (6) , 2007-2012. https://doi.org/10.1007/s00415-020-09950-w
  93. Penghui Wei, Wenyuan Lyu, Tiantian Wan, Qiang Zheng, Wenxi Tang, Jianjun Li, Jian-jun Yang. COVID-19: a novel risk factor for perioperative neurocognitive disorders. British Journal of Anaesthesia 2021, 111 https://doi.org/10.1016/j.bja.2021.06.016
  94. Cinzia Sindona, Giovanni Schepici, Valentina Contestabile, Placido Bramanti, Emanuela Mazzon. NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases. Medicina 2021, 57 (6) , 604. https://doi.org/10.3390/medicina57060604
  95. Mohammad Zarei, Karim Rahimi, Kambiz Hassanzadeh, Mohammad Abdi, Vahedeh Hosseini, Ali Fathi, Karim Kakaei. From the environment to the cells: An overview on pivotal factors which affect spreading and infection in COVID-19 pandemic. Environmental Research 2021, 13 , 111555. https://doi.org/10.1016/j.envres.2021.111555
  96. S. El Mezzeoui, F. Aftissi, M. Aabdi, H. bkiyar, B. Housni. Guillan barre syndrome in post Covid-19 infection in children. Annals of Medicine and Surgery 2021, 395 , 102524. https://doi.org/10.1016/j.amsu.2021.102524
  97. Xiaoming Qi, Kristin A. Keith, Jason H. Huang. COVID-19 and stroke: A review. Brain Hemorrhages 2021, 2 (2) , 76-83. https://doi.org/10.1016/j.hest.2020.11.001
  98. Chin-Chuan Chang, Ming-Hui Yang, Shu-Min Chang, Ya-Ju Hsieh, Che-Hsin Lee, Yi-Ming Arthur Chen, Cheng-Hui Yuan, Yi-Ling Chen, Sheng-Yow Ho, Yu-Chang Tyan. Clinical significance of olfactory dysfunction in patients of COVID-19. Journal of the Chinese Medical Association 2021, Publish Ahead of Print https://doi.org/10.1097/JCMA.0000000000000560
  99. Subash Bhatta, Dibya Sharma, Santosh Sharma, Leison Maharjan, Sushma Bhattachan, Mukesh Kumar Shah, Aditya Singhal, Asheesh Dora Ghanpur, Dushyanth Ganesuni, Shraddha Jayant Saindani. Smell and Taste Disturbance in COVID-19 Patients: A Prospective Multicenteric Review. Indian Journal of Otolaryngology and Head & Neck Surgery 2021, 324 https://doi.org/10.1007/s12070-021-02664-z
  100. Jarosław Wysocki. Otorhinolaryngological manifestations of COVID-19. Polski Przegląd Otorynolaryngologiczny 2021, 10 (2) , 18-24. https://doi.org/10.5604/01.3001.0014.8514
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  • Abstract

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    Figure 1

    Figure 1. Tissue distribution of ACE2 receptors in humans. Viremia (A) disseminates the COVID-19 virus throughout the body via the bloodstream (B). Neurotropism may occur via circulation and/or an upper nasal trancribrial route that enables the COVID-19 to reach the brain (C) and bind and engage with the ACE2 receptors (D, blue). COVID-19 docks on the ACE2 via spike protein (D, golden spikes). Shown are lungs, heart, kidneys, intestines, brain, and testicles that are well-known to express ACE2 receptors and are possible targets of COVID-19.

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    Figure 2

    Figure 2. (A) Sequence alignment of COVID-19 RBD subdomain-1 (319th to 591st) amino acid (top row) with the bat and SARS-CoV spike protein (middle and bottom row) that were fetched from BLASTp results of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acids. Note horizontal arrows that show areas of contrast between the sequences. (A1) Homology modeling of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acid developed a template (6vsb.1. A)-based model of the COVID-19 virus spike glycoprotein. (B). Homology modeling of the COVID-19 virus RBD subdomain-1 (319th to 591st) amino acid developed a template-(5x5b.1.A) based model of the prefusion structure of SARS-CoV spike glycoprotein in conformation 2 (B1) with 73.96% sequence identity. [Uniprot and SWISS-MODEL automated server were used for sequence alignments and development of the templates and models, respectively.]

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    This article references 7 other publications.

    1. 1
      Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, complete genome. Nucleotide, National Center for Biotechnology Information (NCBI), National Library of Medicine (US), National Center for Biotechnology Information, Bethesda, MD, https://www.ncbi.nlm.nih.gov/nuccore/1798174254 (accessed on 2020-02-28).
      Google Scholar
      There is no corresponding record for this reference.
    2. 2
      Palasca, O., Santos, A., Stolte, C., Gorodkin, J., and Jensen, L. J. (2018) TISSUES 2.0: an integrative web resource on mammalian tissue expression. Database 2018, bay003  DOI: 10.1093/database/bay003
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    3. 3
      Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82 (15), 7264– 75,  DOI: 10.1128/JVI.00737-08
      [Crossref], [PubMed], [CAS], Google Scholar
      3
      Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2
      Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, Stanley
      Journal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
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    4. 4
      Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Li, Y., Jin, H., and Hu, B. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv, 2020.02.22.20026500 DOI: 10.1101/2020.02.22.20026500 (accessed on 2020-02-28).
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    5. 5
      Li, Y. C., Bai, W. Z., and Hashikawa, T. (2020) The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients. J. Med. Virol.  DOI: 10.1002/jmv.25728
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    6. 6
      Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., Graham, B. S., and McLellan, J. S. (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science eabb2507  DOI: 10.1126/science.abb2507
      [Crossref], [PubMed], Google Scholar
      There is no corresponding record for this reference.
    7. 7
      Baig, A. M. (2016) Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chem. Neurosci. 7 (8), 1026– 9,  DOI: 10.1021/acschemneuro.6b00197
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      7
      Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri
      Baig, Abdul Mannan
      ACS Chemical Neuroscience (2016), 7 (8), 1026-1029CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      A review. Naegleria fowleri causes one of the most devastating necrotic meningoencephalitis in humans. The infection caused by this free-living amoeba is universally fatal within a week of onset of the signs and symptoms of the disease called primary amoebic meningoencephalitis (PAM). In all the affected patients, there is always a history of entry of water into the nose. Even though the diagnostic and treatment protocols have been revised and improved, the obstinate nature of the disease can be gauged by the fact that the mortality rate has persisted around ∼95% over the past 60 years. Some of the unanswered questions regarding PAM are is there a neurochem. basis of the chemotaxis of N. fowleri to the brain. What immune evasion means occurs preceding the neurotropic invasion. What is the contribution of the acute inflammatory response in the fatal cases. Can a combination of antiamoebic drugs with antagonism of the acute inflammation help save the patient's life. As prevention remains the most valuable safeguard against N. fowleri, a quicker diagnosis, better understanding of the pathogenesis of PAM coupled with testing of newer and safer drugs could improve the chances of survival in patients affected with PAM.
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