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Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID‐19
Open accessAbstract
The new coronavirus, classified as severe acute respiratory syndrome (SARS)-CoV-2 that emerged in Hubei province in China, causes a new coronavirus disease, which was termed COVID-19 by WHO on 11 February 2020. COVID-19 claimed more than 65 000 lives around the world by 5th of April 2020. It is not the first coronavirus, which infects humans; the pathogenic viruses that cause human diseases (human coronaviruses, HCoV) include 6 other members designated as SARS-CoV, middle east respiratory syndrome (MERS)-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43 and HCoV-229E. The clinical presentation is mainly manifested as malignant pneumonia; although many patients present neurological symptoms, such as vomiting, dizziness, headache and delirium.1 Human coronaviruses were first identified in the mid-1960s; they were named for the crown-like spikes on their surface. The SARS-CoV-2 virus belongs to β-coronavirus, which also include MERS-CoV, SARS-CoV-1, NCoV-OC43 and HCoV-HKU1. The primary target cells for SARS-CoV-2 are the epithelial cells of the respiratory and gastrointestinal tract, which contain angiotensin converting enzyme 2 (ACE2), that is utilized by the virus to enter the cell; it is, however, hard to believe that the penetration of the viral agent into the organism is limited only to these tissues.2 Clinical and pre-clinical data from studies with other coronaviruses suggest wider tissue invasiveness and an evident neurotropism, which may result in more complex clinical scenarios. Can the SARS-CoV-2 enter the central nervous system (CNS) and infect neural cells? And if yes, how the CNS damage contributes to pathophysiology of the COVID-19, to its signs, symptoms and progression as well as to its sequelae. In other words, if the SARS-CoV-2 virus had a significant neurotropism, could its presence in the CNS be pathophysiologically relevant? It has been demonstrated that coronaviruses, and especially β-coronaviruses to which the SARS-CoV-2 belongs, do not limit their presence to the respiratory tract and frequently invade the CNS. This propensity has been convincingly documented for the SARS-CoV, MERS-CoV and the coronavirus responsible for porcine haemagglutinating encephalomyelitis (HEV 67N).3-5 Previous findings demonstrate that ACE2 represents the key, but not the exclusive, site of entry of the virus into the cell. The ACE2 is expressed in the brain, being in particularly present in the brain stem and in the regions responsible for regulation of cardiovascular function including subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla; expression of ACE2 was found in both neurones and glia.6, 7 Non-ACE2 pathways for virus infection of neural cells also cannot be excluded; the marked penetration of coronavirus into the liver, an organ with lower levels of ACE 2 compared to the CNS, strongly supports the assumption that the cell entry routes can vary.8 Be this all as it may, the CNS infection with both SARS-CoV-1, MERS-CoV have been reported2 and SARS-CoV-1 has been identified in neurones from tissues obtained from infected patients.9 The intranasal administration of SARS-CoV-110 or MERS-COV11 resulted in the rapid invasion of viral particles into the brain, possibly through the olfactory bulb via trans-synaptic route. This pathway when virus enters peripheral nerves and spreads to the CNS through synaptic contacts has been well-documented for several viruses including CoVs.12 The brainstem, which hosts the respiratory neuronal circuit in the medulla, was severely infected with both types of viruses, which may contribute to degradation and failure of respiratory centres. When the nasal infecting charges were delivered in extremely low doses, only the CNS was colonized, with virus being absent in other tissues including lungs,11 corroborating the potent neurotropism of these coronarovirus strains. This testifies a viral property which cannot be ignored for a complete understanding of the impact of the β-coronaviruses on the human organism. Although direct evidence is currently lacking, the high identity between SARS-CoV-1 and SARS-CoV-2 suggests, that the latter viral strain could also infect the CNS, an ability clearly demonstrated by other members of the family to which they belong. The β-coronavirus NCoV-OC43, which causes upper respiratory tract disorder, has been found to infect neural cell lines as well as primary neurones in culture; it was also found to cause encephalitis associated with neuronal apoptosis and necrosis in mice.13 At least two cases of human encephalitis/encepahlomyelitis caused by NCoV-OC43 were also reported.14, 15 About 12% of children with clinical presentation of acute encephalitis hospitalised at the Children's Hospital of Chenzhou, China between May 2014 and April 2015 had anti-CoV antibodies in serum and in cerebrospinal fluid.16 It is of considerable interest that organ distribution studies have shown that the presence of SARS-C
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“Finally, the cytokine storm theory proposes that SARS-CoV-2 inflammatory response in the CNS is mediated by the massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III [168, 169].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [169]
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“The supposition is that a rapid entry into human host cells is mediated mainly by cellular receptor angiotensin-converting enzyme 2, which is expressed in human airway epithelia, vascular endothelia, and the brain, particularly the brain stem (both in neurons and in glia) (6).”
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“Finally, the cytokine storm theory proposes that SARS-CoV-2 inflammatory response in the CNS is mediated by the massive glial cell cytokine release, such as IL1b, IL-6, and IFN I-III [168, 169].”
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“Previous experiences with SARS-CoV and MERSCoV, as well as experimental data on neurotropic CoVs, have shown that CoV can reach the CNS and infect it (Steardo et al., 2020).”
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“…pain, nausea, delirium, seizures, meningoencephalitis, and impaired consciousness, to Guillain Barré syndrome, peripheral nervous system and skeletal muscle dysfunction/myositis (Mao et al. 2020; Nath 2020; Helms et al. 2020; Toscano et al. 2020; Wu et al. 2020; Baig 2020; Steardo et al. 2020).”
BackgroundSARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury
Fenrich, M., Mrdenovic, S., Balog, M., Tomic, S., Zjalic, M., Roncevic, A., Mandic, D., Debeljak, Z., & Heffer, M. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00229 · Cited by 95
The Impact of SARS-Cov-2 Virus Infection on the Endocrine System
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“integrity of the BBB during severe infection with COVID-19 [20,142].”
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“It is likely that SARS-CoV-2 is capable to make use of one of these (Steardo et al., 2020), but the fact that it can be transferred between neurons is of major concern (Li et al., 2020b).”
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Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options
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Report on Electroencephalographic Findings in Critically Ill Patients with COVID ‐19
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Neurotropic Viruses, Astrocytes, and COVID-19
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“SARS-CoV-2, a human CoV (HCoV) belongs to β-coronaviruses, and various clinical and pre-clinical studies have reported potential neurovirulent properties of these viruses [3].”
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“High prevalence of anosmia and ageusia in absence of nasal obstruction or rhinorrhoea suggest possible sensory neural loss along with trans-nasal transmission, as the underlying cause of the olfactory dysfunction rather than the conductive mechanism seen in most cases of postviral olfactory loss [65, 71, 79].”
BackgroundBrain Mechanisms of COVID-19-Sleep Disorders
Semyachkina-Glushkovskaya, O. V., Mamedova, A., Telnova, V., Klimova, M., Saranceva, E. I., Ageev, V., Yu, T., Zhu, D. Y., Penzel, T., & Kurths, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136917 · Cited by 63
“The resulting neuroinflammatory process may result in severe damage to brain function, as reported in [128,136,137].”
BackgroundApplications of Non-invasive Neuromodulation for the Management of Disorders Related to COVID-19
Baptista, A. F., Baltar, A., Okano, A. H., Moreira, A., Campos, A. C. P., Fernandes, A. M., Brunoni, A. R., Badran, B. W., Tanaka, C., de Andrade, D. C., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.573718 · Cited by 62
“Characterizing the symptoms and etiology of COVID-19 neurological manifestation is complex and subject to ongoing studies, including post-pandemic consequences of the infection, such as encephalitis (70, 71), acute flaccid paralysis (72), acute disseminated encephalomyelitis (19, 73, 74), neuropsychiatric and cognitiv…”
BackgroundNeuropsychiatric manifestations of COVID-19 can be clustered in three distinct symptom categories
Mirfazeli, F. S., Sarabi‐Jamab, A., Jahanbakhshi, A., Kordi, A., Javadnia, P., Shariat, S. V., Aloosh, O., Almasi‐Dooghaee, M., & Faiz, S. H. R. (2020) · Scientific Reports · doi:10.1038/s41598-020-78050-6 · Cited by 60
Costas‐Carrera, A., Sánchez‐Rodríguez, M. M., Cañizares, S., Ojeda, A., Martín‐Villalba, I., Primé‐Tous, M., Rodríguez-Rey, A., Segú, X., Valdesoiro‐Pulido, F., Borràs, R., et al. (2022) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2022.100425 · Cited by 62
“…of COVID-19 have been explained by different mechanisms, including the direct effect of the virus in the Central Nervous System (CNS) via the olfactory bulb (Guedj et al., 2021), neuroin fl ammation, systemic infection, and prolonged hypoxia (Steardo et al., 2020; Miskowiak et al., 2021).”
The close relationship between sudden loss of smell and COVID-19
Joffily, L., Ungierowicz, A., David, A. G., Melo, B., Brito, C. L. T., Mello, L. F., dos Santos, P. D. S. C., & Pezato, R. (2020) · Brazilian Journal of Otorhinolaryngology · doi:10.1016/j.bjorl.2020.05.002 · Cited by 64
Neurotropic Effects of SARS-CoV-2 Modeled by the Human Brain Organoids
Ramani, A., Pranty-Weßelmann, A. I., & Gopalakrishnan, J. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.02.007 · Cited by 52
“Therefore, respiratory insufficiency is notmerely associatedwith lung failure but could also result from the presence of interleukins, tumor necrosis factors, and other cytokines that impair the functioning of the medullary cardiorespiratory center in the brain (Li et al., 2020; Steardo et al., 2020).”
CD38 in the age of COVID-19: a medical perspective
Horenstein, A. L., Faini, A. C., & Malavasi, F. (2021) · Physiological Reviews · doi:10.1152/physrev.00046.2020 · Cited by 53
Neurological complications associated with Covid‐19; molecular mechanisms and therapeutic approaches
Mehrabani, M. M., Karvandi, M. S., Maafi, P., & Doroudian, M. (2022) · Reviews in Medical Virology · doi:10.1002/rmv.2334 · Cited by 53
Rahman, J., Muralidharan, A., Quazi, S. J., Saleem, H., & Khan, S. (2020) · Cureus · doi:10.7759/cureus.8460 · Cited by 49
“The question is this: can SARS-CoV-2 invade the CNS and infect neural cells? Assuming the answer is yes, how does the damage to the CNS contribute to its progression, signs, and symptoms, including consequences [23]?”
BackgroundTargeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19
McGowan, E. M., Haddadi, N., Nassif, N. T., & Lin, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197189 · Cited by 51
“Coronaviruses are historically found to be neurotropic [61].”
BackgroundAutonomic balance determines the severity of COVID-19 courses
Leitzke, M., Stefanovic, D., Meyer, J.-J., Schimpf, S., & Schönknecht, P. (2020) · Bioelectronic Medicine · doi:10.1186/s42234-020-00058-0 · Cited by 49
Kulaga, S. S., & Miller, C. W. T. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.05.008 · Cited by 51
COVID-19 Neurological Manifestations and Underlying Mechanisms: A Scoping Review
Wenting, A., Gruters, A. A. A., van Os, Y., Verstraeten, S., Valentijn, S. A. M., Ponds, R., & de Vugt, M. E. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00860 · Cited by 51
Hernández‐Parra, H., Reyes‐Hernández, O. D., Figueroa‐González, G., Carmen, M. G., González‐Torres, M., Peña‐Corona, S. I., Florán, B., Cortés, H., & Leyva‐Gómez, G. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1125109 · Cited by 51
“Direct CNS infection and systemic inflammation compromise the BBB and trigger a massive neuroinflammatory manifested by reactive astrogliosis and microglia activation (Steardo et al., 2020).”
BackgroundThe Impact of the COVID-19 Pandemic on Dementia Risk: Potential Pathways to Cognitive Decline
Pyne, J. D., & Brickman, A. M. (2021) · Neurodegenerative Diseases · doi:10.1159/000518581 · Cited by 50
“Establishment of delirium and systemic inflammation, both present in severe and critically ill COVID-19 patients, are associated with future risk of dementia [98,132,133].”
BackgroundDas, J. K., Tradigo, G., Veltri, P., Guzzi, P. H., & Roy, S. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa420 · Cited by 44
“Clinical manifestation of COVID19 are large and severe since it seems to impact all the tissues and organs that express ACE2 receptor: severe pneumonia, kidney failure, anemia, neurological problems, cardiovascular complication and a large state of inflammation (know as cytokine storm) in more severe causes [13, 14, 1…”
BackgroundCOVID-19 infection recurrence presenting with meningoencephalitis
Mardani, M., Nadji, S. A., Sarhangipour, K. A., Razavi, A. S., & Baziboroun, M. (2020) · New Microbes and New Infections · doi:10.1016/j.nmni.2020.100732 · Cited by 40
Stoian, A., Stoian, M., Bajkó, Z., Maier, S., Andone, S. R., Cioflinc, R. A., Moțățăianu, A., Bărcuţean, L., & Bălașa, R. (2022) · Biomedicines · doi:10.3390/biomedicines10040774 · Cited by 42
“Neurological complications of COVID-19 may occur as a result of direct virus injury, para- or postinfectious immunemediated or inflammatory reactions triggered by the SARS-CoV-2, or secondary to the systemic inflammatory response syndrome [71,109,115].”
BackgroundAcute meningoencephalitis in a patient with COVID-19
Chaumont, H., Etienne, P., Roze, E. F., Couratier, C., Roger, P., & Lannuzel, A. (2020) · Revue Neurologique · doi:10.1016/j.neurol.2020.04.014 · Cited by 42
“We suspect the meningoencephalitis was related to COVID-19, possibly through a direct infectious mechanism although the virus was not detected in CSF [1].”
InfluentialEmerging Neurological and Psychobiological Aspects of COVID-19 Infection
Tancheva, L. P., Petralia, M. C., Miteva, S., Dragomanova, S., Solak, A., Kalfin, R. E., Lazarova, M. I., Yarkov, D., Ciurleo, R., Cavalli, E., et al. (2020) · Brain Sciences · doi:10.3390/brainsci10110852 · Cited by 43
“The combination of hypoxia with existent neuroinflammation leads to damage in the hippocampal and cortical areas manifesting as the neuropsychiatric effects of the virus [44,87].”
BackgroundLionetti, V., Bollini, S., Coppini, R., Gerbino, A., Ghigo, A., Iaccarino, G., Madonna, R., Mangiacapra, F., Miragoli, M., Moccia, F. D., et al. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105581 · Cited by 44
NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration
Sita, G., Graziosi, A., Hrelia, P., & Morroni, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136984 · Cited by 43
“This infection might slow down respiratory regulation, which, combined with decreased lung activity, may result in a hypoxic condition [111].”
BackgroundAl-Hashel, J., Abokalawa, F., Alenzi, M., Alroughani, R., & Ahmed, S. F. (2021) · The Journal of Headache and Pain · doi:10.1186/s10194-021-01314-7 · Cited by 41
“Another mechanism of COVID-19 viral entry into the brain may be through the olfactory bulb via transsynaptic route [28].”
BackgroundMental health symptoms one year after acute COVID-19 infection: Prevalence and risk factors
Colizzi, M., Peghin, M., Martino, M. D., Bontempo, G., Gerussi, V., Palese, A., Isola, M., Tascini, C., & Balestrieri, M. (2022) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2022.05.008 · Cited by 50
The outlook for diagnostic purposes of the 2019‐novel coronavirus disease
Tahmasebi, S., Khosh, E., & Esmaeilzadeh, A. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29804 · Cited by 41
COVID-19 as a Risk Factor for Alzheimer’s Disease
Golzari-Sorkheh, M., Weaver, D. F., & Reed, M. A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220800 · Cited by 39
“Moreover, the study by Yi and colleagues noted that following COVID-19 infection, elderly individuals with risk factors had a higher rate of developing cerebrovascular disease (CVD) [135].”
BackgroundInfluentialCerebrospinal fluid confirmed COVID-19-associated encephalitis treated successfully
Kamal, Y. M., Abdelmajid, Y., & Madani, A. A. (2020) · BMJ Case Reports · doi:10.1136/bcr-2020-237378 · Cited by 39
Neuropsychology of COVID-19: Anticipated cognitive and mental health outcomes.
Bailey, E. K., Steward, K. A., Jantz, A. B. V., Kamper, J. E., Mahoney, E. J., & Duchnick, J. J. (2021) · Neuropsychology · doi:10.1037/neu0000731 · Cited by 43
New-onset refractory status epilepticus following the ChAdOx1 nCoV-19 vaccine
Aladdin, Y. S., & Shirah, B. H. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577629 · Cited by 40
The Role of Smoking and Nicotine in the Transmission and Pathogenesis of COVID-19
Sifat, A. E., Nozohouri, S., Villalba, H., Vaidya, B., & Abbruscato, T. J. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.120.000170 · Cited by 40
“It has been demonstrated that b -CoVs, to which SARS-CoV-2 belongs, affect the central nervous system (CNS) as well as the respiratory tract (Steardo et al., 2020).”
BackgroundVascular Dysfunctions Contribute to the Long-Term Cognitive Deficits Following COVID-19
Shabani, Z., Liu, J., & Su, H. (2023) · Biology · doi:10.3390/biology12081106 · Cited by 41
Clinical features of SARS-CoV-2-associated encephalitis and meningitis amid COVID-19 pandemic
Huo, L., Xu, K., & Wang, H. (2021) · World Journal of Clinical Cases · doi:10.12998/wjcc.v9.i5.1058 · Cited by 38
Pallanti, S., Grassi, E., Makris, N., Gasic, G. P., & Hollander, E. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.08.008 · Cited by 38
“Although different in mechanism of action and clinical manifestations, an interesting parallelism in the neurological domain, could be drawn with other viruses, which are known for being associated with neurological symptomatology as in Spanish Influenza Pandemic of 1918, and Encephalitis Lethargica, first described b…”
BackgroundNaidu, S. A. G., Wallace, T. C., Davies, K. J. A., & Naidu, A. S. (2021) · Journal of Dietary Supplements · doi:10.1080/19390211.2021.1922567 · Cited by 35
“LF could block viral entry into the host cell, either by binding to cellular receptors, or by direct interaction with the virus particle. may disrupt cardio-respiratory regulation and cause severe pneumonia, and hypoxiamediated brain damage (Steardo et al. 2020).”
BackgroundEndocytic uptake of SARS-CoV-2: the critical roles of pH, Ca2+, and NAADP
Petersen, O. H., Gerasimenko, O. V., & Gerasimenko, J. V. (2020) · Function · doi:10.1093/function/zqaa003 · Cited by 34
Teixeira, T. A., Bernardes, F. S., de Oliveira, Y. R., Hsieh, M. K., Esteves, S. C., Neto, A. N. D., Kallas, E. G., & Hallak, J. (2021) · International braz j urol · doi:10.1590/s1677-5538.ibju.2020.0872 · Cited by 34
“Legends: *DAD = Diffuse alveolar damage; #NETs = neutrophil extracellular traps; §ADEM = Perivascular acute disseminated encephalomyelitis; +ATI: Proximal acute tubule injury; ∞MAC: Membrane attack complex; &SER: Smooth endoplasmic reticulum; &RER = Rough endoplasmic reticulum References: (14, 15, 23, 35, 38-42, 47, 4…”
BackgroundHow Does COVID-19 Affect the Neurobiology of Suicide?
Conejero, I., Nobile, B., Olié, É., & Courtet, P. (2021) · Current Psychiatry Reports · doi:10.1007/s11920-021-01227-x · Cited by 86
Vatsalya, V., Li, F., Frimodig, J., Gala, K. S., Srivastava, S., Kong, M., Ramchandani, V. A., Feng, W., Zhang, X., & McClain, C. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.598128 · Cited by 33
Patel, U. K., Malik, P., Shah, D., Patel, A., Dhamoon, M. S., & Jani, V. B. (2020) · Journal of Neurology · doi:10.1007/s00415-020-10141-w · Cited by 32
Riordan, P., Stika, M. M., Goldberg, J., & Drzewiecki, M. (2020) · The Clinical Neuropsychologist · doi:10.1080/13854046.2020.1810325 · Cited by 34
Xie, J., Tian, S., Liu, J., Cao, R., Yue, P., Cai, X., Shang, Q., Yang, M. H., Han, L., & Zhang, D. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106189 · Cited by 30
Metadata
- Authors
- Steardo, L., Steardo, L., Zorec, R., & Verkhratsky, A.
- Affiliations
- University of Ljubljana (SI)
- Ikerbasque (ES)
- Corresponding author
- Verkhratsky, Alexei
- Venue
- Acta Physiologica
- Publisher
- Wiley
- Published
- 2020-04-11
- Volume
- 229
- Issue
- 3
- Pages
- e13473-e13473
- ISSN
- 1748-1708 (ISSN-L)
- 1748-1716
- PMC
- PMC7228251
- OpenAlex
- W3013521296
- Cited by
- 367
- References
- 31
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 15 · 2023: 52 · 2022: 66 · 2021: 104 · 2020: 116
- FWCI
- 36.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Acta Physiologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository of the University of Ljubljana (University of Ljubljana) (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- COVID-19 pandemic, central nervous system infection, neurotropism, central nervous system infiltration, SARS-CoV-2 pathophysiology, neurological symptoms, ACE2, betacoronaviruses, SARS-CoV-1, MERS-CoV, SARS-CoV-2 pathogenesis, clinical features
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Brain, Central Nervous System Infections, Humans, Peptidyl-Dipeptidase A, Neurons, Pneumonia, Viral, Coronavirus Infections, Pandemics
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