Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanisms
- Abdul Mannan Baig*
Abdul Mannan BaigDepartment of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, PakistanMore by Abdul Mannan Baig
- ,
- Areeba Khaleeq
Areeba KhaleeqDepartment of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, PakistanMore by Areeba Khaleeq
- ,
- Usman Ali
- , and
- Hira Syeda
Hira SyedaDepartment of Biosciences, Mohammad Ali Jinnah University, Karachi 75400, PakistanMore by Hira Syeda
Abstract
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.
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
2. The Genome of the COVID-19 Virus
3. Tissue Distribution of ACE2 in Human Organs and Tissues
3.1. Evidence of the Distribution of ACE2 in the Human Brain
4. Host–Virus Interaction: How the ACE2 Receptor Is Exploited by the COVID-19 Virus to Gain Entry Inside the Host Cells
5. A Proposed Cascade of Cerebral Involvement in the COVID-19 Infections
6. Conclusions and Future Directions
Acknowledgments
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
This article references 7 other publications.
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7Baig, A. M. (2016) Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chem. Neurosci. 7 (8), 1026– 9, DOI: 10.1021/acschemneuro.6b00197Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2lsb7I&md5=715fbdb82bc345f03c187d02ded6e057Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleriBaig, Abdul MannanACS 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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This article references 7 other publications.
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1Wuhan 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).There is no corresponding record for this reference.
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3Netland, 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.00737-083https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovVSltr4%253D&md5=b5d85df75cb9f2ab540c952704ff5377Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, StanleyJournal 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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4Mao, 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).There is no corresponding record for this reference.
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5Li, 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.25728There is no corresponding record for this reference.
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6Wrapp, 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.abb2507There is no corresponding record for this reference.
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7Baig, A. M. (2016) Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chem. Neurosci. 7 (8), 1026– 9, DOI: 10.1021/acschemneuro.6b001977https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtF2lsb7I&md5=715fbdb82bc345f03c187d02ded6e057Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleriBaig, Abdul MannanACS 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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