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

Ali, Usman

Baig, Abdul Mannan

Khaleeq, Areeba

Syeda, Hira

English

Crossref

eCommons@AKU

1 Evidence of the COVID-19 Virus Targeting the CNS: Tissue2 Distribution, Host−Virus Interaction, and Proposed Neurotropic3 Mechanisms4 Abdul Mannan Baig,* Areeba Khaleeq, Usman Ali, and Hira SyedaCite This: https://dx.doi.org/10.1021/acschemneuro.0c00122 Read OnlineACCESS Metrics & More Article Recommendations5 ABSTRACT: The recent outbreak of coronavirus infectious disease 20196 (COVID-19) has gripped the world with apprehension and led to a scare of7 epic proportions related to its potential to spread and infect humans worldwide. As8 we are in the midst of an ongoing near pandemic outbreak of COVID-19, scientists9 are struggling to understand how it resembles and varies with the severe acute10 respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic11 level. In a short time following the outbreak, it has been shown that, similar to12 SARS-CoV, COVID-19 exploits the angiotensin-converting enzyme 2 (ACE2)13 receptor to gain entry inside the cells. This finding raises the curiosity of14 investigating the expression of ACE2 in neurological tissue and the possible15 contribution of neurological tissues damage to the morbidity and mortality of16 COIVD-19. Here, we investigate the density of the expression levels of ACE2 in17 the CNS and the host−virus interaction and relate it to the pathogenesis and18 complications seen in recent cases of the COVID-19 outbreak. Also, we debate the need for a model of staging COVID-19 based on19 neurological tissue involvement.20 KEYWORDS: Coronavirus, COVID-19, tissue distribution, host−virus interaction, proposed mechanisms1. THE NOVEL COVID-19 VIRUS21 The first reports of a viral infection attracted attention in late22 December 2019 in Wuhan, the capital of Hubei, China. Later,23 it was revealed that the virus responsible for causing the24 infections was contagious between humans. In early January,25 the terms like “the new coronavirus” and “Wuhan coronavirus”26 were in common use. On February 11, 2020, a taxonomic27 designation “severe acute respiratory syndrome coronavirus 2″28 (SARS-CoV-2) became official in order to refer to the virus29 strain, that was previously termed as 2019-nCoV and Wuhan30 coronavirus. Within a few hours on the same day, the WHO31 officially renamed the disease as COVID-19.2. THE GENOME OF THE COVID-19 VIRUS32 The complete genome of COVID-19 virus from Wuhan, China33 was submitted on January 17, 2020 in the National Center for34 Biotechnology1 (NCBI) database, with ID NC_045512. It is a35 29,903 bp single-stranded RNA (ss-RNA) coronavirus. It has36 now been shown that COVID-19 is a SARS-like coronavirus37 that had previously been reported in bats in China.3. THE TISSUE DISTRIBUTION OF ACE2 IN HUMAN38ORGANS AND TISSUES39In order to discover the neurological pathogenic potential of40COVID-19 and relate it to neurological tissue expression of41ACE2, data retrieval was done from human protein databases.42 f1Most of the evidence of ACE2 expression in the brain (Figure43 f11) comes from literature and mammalian tissue expression44databases,2 which prompted us to investigate neurotropic45effects of COIVD-19 and its contribution toward the morbidity46and mortality of patients with COVID-19.473.1. Evidence of the Distribution of ACE2 in the48Human Brain. The brain has been reported to express ACE249receptors (Figure 1A, C) that have been detected over glial50cells and neurons, which makes them a potential target of51COVID-19. Previous studies have shown the ability of SARS-52CoV to cause neuronal death in mice by invading the brain via53the nose close to the olfactory epithelium.3 The contribution ofReceived: March 1, 2020Accepted: March 3, 2020Viewpointpubs.acs.org/chemneuro© XXXX American Chemical SocietyAhttps://dx.doi.org/10.1021/acschemneuro.0c00122ACS Chem. Neurosci. XXXX, XXX, XXX−XXXdrh00 | ACSJCA | JCA11.2.5208/W Library-x64 | manuscript.3f (R5.0.i3:5004 | 2.1) 2020/02/05 13:43:00 | PROD-WS-116 | rq_4943157 | 3/05/2020 15:08:30 | 4 | JCA-DEFAULT54 neural targeting of COVID-19 in patients reported in the55 recent outbreak remains to be established. In the SARS-CoV56 infections reported in the past, autopsy findings of the patients57 have shown the evidence-based presence of SARS-CoV via58 electron microscopy, immunohistochemistry, and real-time59 reverse transcription-PCR 3. Patients with acute SARS-CoV60 illness have also shown the presence of the virus in61 cerebrospinal fluid. The role of the blood-brain barrier in62 containing the virus and preventing it from gaining access to63 the neural tissues needs to be further explored in COVID-19.64 Recently, a study posted in medRxiv4 has reported neurological65 manifestations in COVID-19 in the current outbreak that66 involved 214 patients, of which 78 (36.4%) patients had67 neurologic manifestations, which affirms our rationale of the68 neurotropic potential in the COVID-19 virus. Also, a finding69 published on a patient who had loss of involuntary control over70 breathing5 during the recent outbreak implores healthcare71 professionals and clinicians to segregate COVID-19 patients72 into neurologically affected cases and those who are devoid of73 neurological deficits.4. HOST−VIRUS INTERACTION: HOW THE ACE274 RECEPTOR IS EXPLOITED BY THE COVID-19 VIRUS75 TO GAIN ENTRY INSIDE THE HOST CELLS76 With the mRNA encoding 12 proteins,1 the COVID-19 virus,77 like SARS-CoV, uses a spike protein S1 that enables the78 attachment of the virion to the cell membrane by interacting79 with host ACE2 receptor3,6 (Figure 1C, D). In the later study,680 it was shown that the ACE2 binding affinity of the 2019-nCoV81 spike protein ectodomain was 10−20-fold higher than ACE282 binding to SARS-CoV spike protein. A BLASTp search of the83 COVID-19 RBD subdomain-1 (319th to 591st aa) fetched a84 spike glycoprotein [bat coronavirus RaTG13] and S1 protein85 and partial [SARS coronavirus GD322] as a homologue.86 Pairwise sequence alignments of the three sequences show that87 though the spike proteins of all three CoV are highly similar,f2 88 they are not identical (Figure 2A, horizontal arrows), which89may be the reason for the higher binding affinity of the90COVID-19 spike protein to the human ACE2 receptor.91Homology modeling of COVID-19 RBD subdomain-1 (319th92to 591st aa) in the SWISS-MODEL automated server93developed a template-based model of the 2019-nCoV94(COVID-19) spike glycoprotein with a single receptor-binding95domain up configuration (Figure 2A1) with 100% sequence96identity. Of the other template-based models developed, it97expectedly showed a model of the structure of the SARS-CoV98spike glycoprotein, conformation 2 with about 74% sequence99identity (Figure 2B, B1), which shows them to be structurally100and evolutionarily related.5. A PROPOSED CASCADE OF CEREBRAL101INVOLVEMENT IN THE COVID-19 INFECTIONS102The dissemination of COVID-19 in the systemic circulation or103across the cribriform plate of the ethmoid bone (Figure 1)104during an early or later phase of the infection can lead to105cerebral involvement as has been reported in the past for106SARS-CoV affected patients.3 The presence of COVID-19 in107general circulation understandably enables them to pass into108the cerebral circulation (Figure 1A−C) where the sluggish109movement of the blood within the microcirculation could be110one of the factors that could facilitate the interaction of the111COVID-19 virus with ACE2 expressed in the capillary112endothelium. Subsequent budding of the viral particles from113the capillary endothelium and damage to the endothelial lining114can favor viral access to the brain (Figure 1B). Other possible115mechanisms like the transendothelial migration of the virus can116also enable virus entry into the brain. Once with the milieu of117the neuronal tissues, its interaction with ACE2 receptors118(Figure 1C, D) expressed in neurons2 can initiate a cycle of119viral budding accompanied by neuronal damage without120substantial inflammation as has been seen with cases of121SARS-CoV3 in the past. It is important to mention here that,122long before the proposed anticipated neuronal damages occur,123the endothelial ruptures in capillaries accompanied by bleedingFigure 1. Tissue distribution of ACE2 receptors in humans. Viremia (A) disseminates the COVID-19 virus throughout the body via thebloodstream (B). Neurotropism may occur via circulation that enables the COVID-19 to reach the brain (C) and bind and engage with the ACE2receptors (D, blue). COVID-19 docks on the ACE2 via spike protein (D, golden spikes). Shown are lungs, heart, kidneys, intestines, brain, andtesticles that are well-known to express ACE2 receptors and are possible targets of COVID-19.ACS Chemical Neuroscience pubs.acs.org/chemneuro Viewpointhttps://dx.doi.org/10.1021/acschemneuro.0c00122ACS Chem. Neurosci. XXXX, XXX, XXX−XXXB124 within the cerebral tissue can have fatal consequences in125 patients with COIVD-19 infections. The movement of the126 COVID-19 virus to the brain via the cribriform plate close to127 the olfactory bulb can be an additional pathway of the virus to128 affect the brain, and finding of an altered sense of smell or129 hyposmia in an uncomplicated early stage COVID-19 patient130 should be investigated thoroughly for CNS involvement.6. CONCLUSIONS AND FUTURE DIRECTIONS131 Autopsies of the COVID-19 patients, detailed investigation,132 and attempts to isolate COVID-19 from the endothelium of133 cerebral microcirculation, cerebrospinal fluid, glial cells, and134 neuronal tissue can clarify the role played by this novel135 COVID-19 coronavirus in the mortalities observed in the136 recent outbreak. It is important to mention here that though137 the cerebral damage may complicate a COVID-19 infection, it138 appears that it is the widespread dysregulation of the139 homeostasis caused by pulmonary, renal, cardiac, and140 circulatory damage that proves fatal in COIVD-19 patients.141 With that being said, a dominant cerebral involvement alone142 with the potential of causing cerebral edema in COVID-19 can143 take a lead in causing death long before systemic homeostatic144dysregulation sets in. Access of COVID-19 to the brain via the145transcribrial route, as described previously for other CNS146targeting pathogens,7 appears to be the case in a recently147reported patient with hyposmia,5 which needs to be further148investigated by attempting to isolate the COVID-19 virus from149zones in proximity to the olfactory bulb. The differences in the150spike proteins of COVID-19 and SARS-CoV (Figure 2A) may151enable scientists to exploit the contrast in sequences in order to152identify epitopes in COVID-19 for the development of153monoclonal antibodies against this virus. With the recent154COVID-19 outbreak, there is an urgent need to understand the155neurotropic potential of the COVID-19 virus in order to156prioritize and individualize the treatment protocols based on157the predominant organ involvement. Also, a staging system158based on the severity and organ involvement is needed for159COVID-19 in order to rank the patients for aggressive or160conventional treatment modalities.161■ AUTHOR INFORMATION162Corresponding Author163Abdul Mannan Baig − Department of Biological and164Biomedical Sciences, Aga Khan University, Karachi 74800,Figure 2. (A) Sequence alignment of COVID-19 RBD subdomain-1 (319th to 591st) amino acid (top row) with the bat and SARS-CoV spikeprotein (middle and bottom row) that were fetched by BLASTp results of COVID-19 RBD subdomain-1 (319th to 591st) amino acids. Notehorizontal arrows that show areas of contrast. (A1) The homology modeling of COVID-19 RBD subdomain-1 (319th to 591st) amino aciddeveloped a template (6vsb.1. A)-based model of the 2019-nCoV (COVID-19) spike glycoprotein with a single receptor-binding domain upconfiguration. (B). Homology modeling of COVID-19 RBD subdomain-1 (319th to 591st) amino acid developed a template-(5x5b.1.A) basedmodel 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.]ACS Chemical Neuroscience pubs.acs.org/chemneuro Viewpointhttps://dx.doi.org/10.1021/acschemneuro.0c00122ACS Chem. Neurosci. XXXX, XXX, XXX−XXXC165 Pakistan; orcid.org/0000-0003-0626-216X; Phone: +92-166 (0)333-2644-246; Email: abdul.mannan@aku.edu167 Authors168 Areeba Khaleeq − Department of Biological and Biomedical169 Sciences, Aga Khan University, Karachi 74800, Pakistan170 Usman Ali − Department of Biological and Biomedical Sciences,171 Aga Khan University, Karachi 74800, Pakistan172 Hira Syeda − Department of Biological and Biomedical Sciences,173 Aga Khan University, Karachi 74800, Pakistan174 Complete contact information is available at:175 https://pubs.acs.org/10.1021/acschemneuro.0c00122176 Funding177 This project was partly funded by Aga Khan University.178 Notes179 The authors declare no competing financial interest.180 ■ ACKNOWLEDGMENTS181 The authors would like to thank the staff and faculty members182 of the Department of Biological & Biomedical Sciences, Aga183 Khan University, who, despite their busy schedule, made it to184 the COVID-19 presentations made by the authors and185 provided us with their critical review on the rationale of this186 study.187 ■ REFERENCES(1)188 Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1,189 complete genome. Nucleotide, National Center for Biotechnology190 Information (NCBI), National Library of Medicine (US), National191 Center for Biotechnology Information, Bethesda, MD, https://www.192 ncbi.nlm.nih.gov/nuccore/1798174254 (accessed on 2020 Apr 06).(2)193 Palasca, O., Santos, A., Stolte, C., Gorodkin, J., and Jensen, L. J.194 (2018) TISSUES 2.0: an integrative web resource on mammalian195 tissue expression. Database 2018, No. bay003.(3)196 Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and197 Perlman, S. (2008) Severe acute respiratory syndrome coronavirus198 infection causes neuronal death in the absence of encephalitis in mice199 transgenic for human ACE2. J. Virol. 82 (15), 7264−75.(4)200 Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., Zhou,201 Y., Wang, D., Li, Y., Jin, H., and Hu, B.Neurological Manifestations of202 Hospitalized Patients with COVID-19 in Wuhan, China: a203 retrospective case series study. medRxiv, 2020.02.22.20026500.(5)204 Li, Y. C., Bai, W. Z., and Hashikawa, T. (2020) The205 neuroinvasive potential of SARS-CoV2 may be at least partially206 responsible for the respiratory failure of COVID-19 patients. J. Med.207 Virol., DOI: 10.1002/jmv.25728.(6)208 Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.209 L., Abiona, O., Graham, B. S., and McLellan, J. S. (2020) Cryo-EM210 structure of the 2019-nCoV spike in the prefusion conformation.211 Science, No. eabb2507.(7)212 Baig, A. M. (2016) Primary Amoebic Meningoencephalitis:213 Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri.214 ACS Chem. Neurosci. 7 (8), 1026−9.ACS Chemical Neuroscience pubs.acs.org/chemneuro Viewpointhttps://dx.doi.org/10.1021/acschemneuro.0c00122ACS Chem. Neurosci. XXXX, XXX, XXX−XXXD

Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

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Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

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