| Article Access Statistics|
| Viewed||1817 |
| Printed||69 |
| Emailed||0 |
| PDF Downloaded||95 |
| Comments ||[Add] |
Click on image for details.
|Year : 2020 | Volume
| Issue : 2 | Page : 274-275
Do SARS-CoV2 Viral Proteins have Neuromodulatory Properties?
Jyotirmoy Banerjee1, Manjari Tripathi2, P Sarat Chandra3, Aparna Banerjee Dixit4
1 Center of Excellence for Epilepsy; Department of Biophysics, AIIMS, Delhi, India
2 Center of Excellence for Epilepsy; Department of Neurology, AIIMS, Delhi, India
3 Center of Excellence for Epilepsy; Department of Neurosurgery, AIIMS, Delhi, India
4 Center of Excellence for Epilepsy, AIIMS; Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
|Date of Web Publication||15-May-2020|
Aparna Banerjee Dixit
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Banerjee J, Tripathi M, Chandra P S, Dixit AB. Do SARS-CoV2 Viral Proteins have Neuromodulatory Properties?. Neurol India 2020;68:274-5
The novel (coronavirus disease 2019 [COVID-19)) has caused a pandemic outbreak of severe pneumonia initially emerged in December 2019 in Wuhan, China, and rapidly spreading around the world. Recent WHO worldwide reports include 25,65,059, confirmed cases out of which 6,86,634 people have recovered and 1,77,496 people have died. As of now, reports from India include 19,984 confirmed cases, out of which 3,870 people have recovered and 640 people have died (WHO, 2020). Acute respiratory distress in humans is one of the major symptoms of patients infected with coronaviruses (CoVs), which are large enveloped non-segmented positive-sense RNA viruses. All CoVs were found to be contagious between humans, with few CoVs such as hCoV-229E, NL63, HKU1, and OC43 are mild whereas severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) have high transmission rate and high mortality. The complete genome sequence of SARS-CoV-2 from Wuhan, China (ID NC_045512) is now available in the National Center for Biotechnology (NCBI) database, with ID NC_045512. The genome of SARS-CoV-2 is a 29,903 bp single-stranded RNA (ss-RNA) coronavirus. All the CoVs have similar viral structures and routes of infection, therefore, it may be possible that infection pathways reported for other CoVs may also hold true for SARS-CoV-2.
One school of thought suggests that neurotropism is a common finding for CoVs. Thus, it is warranted to know if SARS-CoV-2 can affect the central nervous system (CNS), causing neuronal injury resulting in acute respiratory distress along with other neurological deficits.,,,, The latency period of SARS-CoV-2 may be enough to affect neurons. Severe patients infected with SARS-CoV-2 displayed neurologic manifestations. One patient was found to lose involuntary control over breathing with several other patients suffering from acute respiratory failure in the recent outbreak in China. Recently, one study on 214 COVID-19 patients further found that about 88% (78/88) among the severe patients displayed neurologic manifestations including acute cerebrovascular diseases and impaired consciousness. More recently, another study reported the first case showing an association between frequent seizures and COVID-19.
Scientists all over the world are trying to understand the commonality and differences between various SARS-CoVs at the genomic, transcriptomic, and proteomic levels. Various reports on recent cases resulting from the COVID-19 outbreak suggests that similar to SARC-CoV, COVID-19 virus also exploits angiotensin-converting enzyme-2 (ACE2) receptor to gain entry inside the cells.
The exact route by which SARS-CoV or MERS-COV enters the CNS is still not reported. Increasing evidence suggests that CoVs may invade through peripheral sensory or motor nerve terminals, and then gain access to the CNS via a synapse or trans-synapse route using clathrin-coating-mediated endocytotic/exocytotic pathway, as documented earlier for other CoVs, such as HEV67N and avian bronchitis virus.,, One study reported that when the avian influenza virus was intranasally inoculated in mice, besides bronchitis or pneumonia the mice also developed a neural infection. Viral antigens have been detected in the brainstem, where the infected regions included the nucleus of the solitary tract and nucleus ambiguous, suggesting that respiratory failure in infected animals or patients may be due to the dysfunction of the cardiorespiratory center in the brainstem. However, no studies have been reported so far on the mechanism of neuromodulation in CNS by COVID 19.
Recently Gordon et al. have identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). They performed host-virus protein interaction studies by expressing various open reading frames (ORFs) of COVID-19 in HEK293 cells, including 16 nonstructural proteins (Nsp1-16) which form the replicase/transcriptase complex (RTC), four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) 17, and nine putative accessory factors.
Two proteins, the spike protein (S) and main protease Nsp5 are potential molecules as a prominent number of interactions were related to lipid modifications and vesicle trafficking to S protein whereas Nsp5 showed high confidence interaction with the epigenetic regulator histone deacetylase 2 (HDAC2). Both these molecules are potential targets for therapeutic inhibition as on one hand lipid modulation can promote neuroinvasion and on the other hand, HDAC2 which is highly expressed in neuronal tissues plays a crucial role in CNS development and is a potential therapeutic target of neurodegenerative diseases.
There is an urgent need to understand the neurotropic potential of the COVID-19 virus by understanding the possible mechanism of neuromodulation which will be significant for the prevention and treatment of the SARS-CoV-2-induced respiratory failure. In the current scenario, various research strategies need to be employed to understand the mechanisms of neuromodulation resulting either directly in respiratory failure or causing neurological deficits.
Such strategies could be (1) detailed neurological investigations and isolation of SARS-CoV-2 from different regions of the brain such as cerebrospinal fluid, glial cells, neuronal tissue and blood samples of autopsies of the COVID-19 patients (2) Host-virus interaction studies using either omics approach (genomic/transcriptomic/proteomic/lipidomic/metabolomic) or cloning and expressing individual COVID-19 proteins in different neuronal cell lines followed by pull-down assays and mass spectrometry and analyzing the interacting protein network. Further proteomic/chemoinformatic analysis can help in identifying already available drugs and clinical molecules from the databases that might interfere with the viral-human interactome.
| » References|| |
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al
. A new coronavirus associated with human respiratory disease in China. Nature 2020;579:265-9.
De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses. Nat Rev Microbiol 2016;14:523-34.
Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al
. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg. Microbes Infect 2020;9:221-36.
Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020;1:995-8.
Ling M, Mengdie W, Shanghai C, Quanwei H, Jiang C, Candong H, et al
. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: A retrospective case series study. medRxiv. doi: https://doi.org/10.1101/2020.02.22.20026500
Karimi N, Sharifi Razavi A, Rouhani N. Frequent convulsive seizures in an adult patient with COVID-19: A case report. Iran Red Crescent Med J 2020;22:e102828.
Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020. doi: 10.1002/jmv. 25728.
Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M, Talbot PJ. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol 2018;92. doi: 10.1128/JVI.00404-18.
Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O'Meara MJ, et al
. A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing. bioRxiv 2020. doi: 10.1101/2020.03.22.002386.
Choubey SK, Jeyakanthan J. Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor – A novel target to prevent Alzheimer's disease. J Recept Signal Transduct 2018;38:266-78.