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Id Subject Object Predicate Lexical cue
T1 0-78 Sentence denotes Central neurological complications and potential neuropathogenesis of COVID-19
T2 80-92 Sentence denotes Dear Editor,
T3 93-194 Sentence denotes In December 2019, a new corona virus pneumonia (COVID-19) first broke out and soon reached worldwide.
T4 195-307 Sentence denotes The causative pathogen is SARS-CoV-2, which is recognized as the 7th member of human corona virus (HCoV) family.
T5 308-461 Sentence denotes Approximately, 8 months of COVID-19 rapid spreading has led to over 10 million diagnosed cases and hundreds of thousand fatalities in multiple countries.
T6 462-713 Sentence denotes The World Health Organization (WHO) has characterized the COVID-19 outbreak as a “Public Health Emergency of International Concern”, and it’s the first pandemic caused by a corona virus, which poses an imminent threat to the global health care system.
T7 714-747 Sentence denotes SARS-CoV-2 is a beta-coronavirus.
T8 748-998 Sentence denotes The spike glycoprotein of SARS-CoV-2 can attach to host cell membrane by recognizing and binding to the angiotensin-converting enzyme 2 (ACE2) receptor, and transmembrane protease type 2 (TMPRSS2) also plays a critical role in the viral invasion [1].
T9 999-1215 Sentence denotes Based on the homology modeling of receptor binding domain subdomain-1, the structure of SARS-CoV-2 shows about 73.96% sequence identity with SARS-CoV, which might explain the resemblance in biochemical mechanism [2].
T10 1216-1400 Sentence denotes SARS-CoV-2 has been reported to exert toxic effects on multiple tissues and organs, such as lung, heart, esophagus, kidney, bladder, ileum, as well as the central nervous system (CNS).
T11 1401-1625 Sentence denotes According to a study in Wuhan, dizziness (16.8%) and headache (13.1%) are the most common CNS symptoms, followed by impaired consciousness (7.5%), acute cerebrovascular disease (2.8%), ataxia (0.5%), and seizures (0.5%) [3].
T12 1626-1714 Sentence denotes In another study outside of Wuhan, the incidence of headache even reaches up to 34% [4].
T13 1715-2095 Sentence denotes Although there’s no direct evidence supporting a specific relationship between SARS-CoV-2 and human neuropathology, a spectrum of central neurological manifestations of COVID-19 have already been described in case reports and retrospective studies, including encephalitis, meningitis, encephalopathy, acute disseminated encephalomyelitis (ADEM), and acute cerebrovascular disease.
T14 2096-2208 Sentence denotes The corresponding neuropathologic changes are also observed in the COVID-19 patients at autopsy [5–9] (Table 1).
T15 2209-2307 Sentence denotes Table 1 Neurological manifestations and associated neuropathological findings in COVID-19 patients
T16 2308-2388 Sentence denotes Manifestations Presentations Neuropathological findings Type of study References
T17 2389-2592 Sentence denotes Encephalitis/meningitis Three out of six patients presented with somnolent Cerebral cortex encephalitis with perivascular and parenchymal inflammatory infiltrates, and shrunken neurons Correspondence [5]
T18 2593-2804 Sentence denotes Encephalopathy Four out of 18 patients presented with myalgia, headache, and decreased taste, progressed to consciousness and multiorgan failure Hypoxic changes with no specific pathology Retrospective study [6]
T19 2805-3056 Sentence denotes Acute disseminated encephalomyelitis Fatigue and exertional dyspnea, progressed to shock state, respiratory failure Features resembling both vascular and demyelinating aetiologies among with range of sub-cortical white matter pathology Case report [7]
T20 3057-3315 Sentence denotes Acute cerebrovascular disease 17 patients presented with cerebral ischaemia, five with intracerebral haemorrhage and one with leukoencephalopathy of posterior reversible encephalopathy Thrombotic microangiopathy and endothelial injury Retrospective study [8]
T21 3316-3421 Sentence denotes Two patient presented with coma and multiorgan failure Microthrombi and acute infarcts Correspondence [9]
T22 3422-3658 Sentence denotes Based on the experience of other HCoVs, there are three potential factors related to neurological manifestations: direct invasion by virus, host immune response after infection, as well as the associated pulmonary and systemic diseases.
T23 3659-3871 Sentence denotes The damage of direct invasion depends (in part) on the ability of virus to penetrate the CNS (neuroinvasion), infect neurons and glial cells (neurotropism), and induce neurological diseases (neurovirulence) [10].
T24 3872-4045 Sentence denotes It still remains unclear to what extent the CNS symptoms can be attributed to direct SARS-CoV-2 invasion or if these symptoms are mainly related to the secondary mechanisms.
T25 4046-4209 Sentence denotes Several HCoVs, such as HCoV-229E, HCoV-OC43, and SARS-CoV, are considered to be neuroinvasive since the infectious particles or viral RNAs are detected in the CNS.
T26 4210-4325 Sentence denotes They act typically by two anatomical routes: hematogenous dissemination and neuronal retrograde dissemination [10].
T27 4326-4659 Sentence denotes Once the HCoVs reaching cerebral circulation by hematogenous dissemination during viremia, the viruses may penetrate the blood–brain barrier (BBB) through receptors expressed on the brain micro-vascular endothelial cells and subsequently impair the endothelial cell–cell junctions, resulting in BBB dysfunction and hyperpermeability.
T28 4660-4767 Sentence denotes HCoVs may pass the BBB by hijacking host immunocytes as well, which is termed “the Trojan horse mechanism”.
T29 4768-4993 Sentence denotes Recently, the presence of SARS-CoV-2 viral-like particles has been observed in capillary endothelia of a frontal lobe specimen [11], and the entry of SARS-CoV-2 into the CNS via endothelial cells has also been documented [5].
T30 4994-5087 Sentence denotes These results indicate that the hematogenous dissemination can be a potential route of entry.
T31 5088-5185 Sentence denotes It remains unclear whether SARS-CoV-2 is able to penetrate the CNS via neuronal retrograde route.
T32 5186-5326 Sentence denotes Olfactory dysfunction is one of the most common symptoms in COVID-19, which is often related to viral infection of the olfactory epithelium.
T33 5327-5608 Sentence denotes But according to the Human Protein Atlas (HPA) database, it is non-neuronal cells (for example, olfactory epithelial support cells, stem cells, and vascular pericytes) that express ACE2 and are vulnerable to SARS-CoV-2 infection, rather than olfactory sensory or bulb neurons [12].
T34 5609-5819 Sentence denotes Primary infection of non-neuronal cells possibly causes olfactory dysfunction by leading to significant inflammatory responses, altering the function of olfactory neurons, and influencing the olfactory signals.
T35 5820-5939 Sentence denotes Besides, no specific changes referable to the virus have been observed in the olfactory bulbs or tracts at autopsy [6].
T36 5940-6087 Sentence denotes Thus, further studies may be needed to determine whether there are other neuronal pathways, such as nerves from the lung or gastrointestinal tract.
T37 6088-6233 Sentence denotes Cases have emerged in which patients had clinical manifestations of encephalitis and positive results of SARS-CoV-2 in cerebrospinal fluid (CSF).
T38 6234-6402 Sentence denotes However, these findings cannot prove the neurotropism of SARS-CoV-2 directly, since the CSF may also contain the virus from the meninges and cerebral microvasculatures.
T39 6403-6588 Sentence denotes In fact, based on the HPA and Genotype Tissue Expression (GTEx) databases, the CNS cells express rather low levels of TMPRSS2, which are required by SARS-CoV-2 for host cell entry [12].
T40 6589-6749 Sentence denotes Lately, Bullen et al. reported the potential neurotropism of SARS-CoV-2 by employing a human induced pluripotent stem cell (iPSC)-derived BrainSphere mode [13].
T41 6750-6916 Sentence denotes Virus infection and replication can be observed in BrainSphere despite the TMPRSS2 gene expression being below the detection limit, suggesting alternative processing.
T42 6917-6988 Sentence denotes In fact, a few proteins are found to act as co-factors for viral entry.
T43 6989-7214 Sentence denotes A Disintegrin and Metalloproteases 17 (ADAM17) is a co-factor that can compete with TMPRSS2 or work independently for ACE2 shedding, and down regulation of ADAM17 by siRNA may result in a decreased in SARS-CoV infection [14].
T44 7215-7316 Sentence denotes According to HPA database, ADAM17 is more widely distributed than TMPRSS2 in human brain tissue [12].
T45 7317-7405 Sentence denotes Nevertheless, it should be emphasized that the current information is far from complete.
T46 7406-7703 Sentence denotes Several aspects still remain to be elucidated before drawing a final conclusion about the neurotropism of SARS-CoV-2, such as the potential host receptors and infection co-factors, the susceptibility of CNS resident cells, as well as possible host–pathogen interactions on ACE2/TMPRSS2 expression.
T47 7704-7852 Sentence denotes Viral infection is often associated with cell death, and numerous molecular pathways have been proposed to explain the neurovirulence of HCoVs [10].
T48 7853-7996 Sentence denotes For example, parthanatos, caspase independent-apoptosis and programmed necrosis pathways may be involved in the neuropathogenesis of HCoV-OC43.
T49 7997-8275 Sentence denotes These molecular pathways can also interact with one other by sharing the same cellular factors (such as calcium overload, mitochondrial dysfunction or endoplasmic reticulum stress, excitatory amino acid toxicity), and active compounds (such as reactive oxygen species) (Fig. 1).
T50 8276-8374 Sentence denotes However, it remains to be determined whether and how SARS-CoV-2 affects the function of CNS cells.
T51 8375-8479 Sentence denotes Fig. 1 HCoVs probably exhibit neuropathological consequences through multiple routes. ① Direct invasion.
T52 8480-8593 Sentence denotes After invasion, the production and release of virus may induce cell death by several pathways. ② Immune response.
T53 8594-8808 Sentence denotes The virus can lead to over-activation of host immune response, releasing a large number of pro-inflammatory cytokines and chemokines (e.g., IL-6, IL-1β, IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, CCL3, and TNF).
T54 8809-8927 Sentence denotes Cytokine signal pathways will subsequently induce the cell death and tissue damage. ③ Neuroendocrine-immune crosstalk.
T55 8928-9043 Sentence denotes Aberrant release of neuropeptides from the infected neurons may act at the endocrine glands, such as adrenal gland.
T56 9044-9191 Sentence denotes These neuropeptides might cause anomalous release of glucocorticoids and other peptides, which may contribute to the dysregulation of immune system
T57 9192-9256 Sentence denotes Meanwhile, SARS-CoV-2 can contribute to CNS symptoms indirectly.
T58 9257-9388 Sentence denotes It is known that cytokine storm syndrome and immunosuppression are important factors accelerating the progression of COVID-19 [15].
T59 9389-9542 Sentence denotes Some HCoVs can contribute to CNS demyelinating diseases by triggering immune dysfunction, and similar cases have been reported in SARS-CoV-2 as well [7].
T60 9543-9680 Sentence denotes A 71-year-old man, who had been hospitalized for cardiac disease initially, was diagnosed with COVID-19 and died after more than 2 weeks.
T61 9681-9854 Sentence denotes In the subsequent post-mortem analysis, pathologic changes have been observed in the brain tissue with features resembling both acute hemorrhagic leukoencephalitis and ADEM.
T62 9855-10052 Sentence denotes This indicates that SARS-CoV-2 may induce CNS tissue damage though cytokine pathways and the patients who burdened by severe infection might be more prone to serious neuropathological consequences.
T63 10053-10310 Sentence denotes In turn, viral infection of CNS may also lead to the impairment of immune response, partly because the virus can influence the neuroendocrine system in releasing glucocorticoids and other peptides, which is called “neuroendocrine-immune crosstalk” (Fig. 1).
T64 10311-10546 Sentence denotes Besides, an autopsy of 18 COVID-19 patients showed that only hypoxic changes, rather than specific changes referable to viral infection, have been observed in the brain specimens, even in some patients presenting with CNS symptoms [6].
T65 10547-10693 Sentence denotes This is partly because SARS-CoV-2 infection is often associated with pulmonary and systemic diseases that may lead to neurological manifestations.
T66 10694-10799 Sentence denotes In conclusion, the SARS-CoV-2 may trigger or exacerbate neuropathologies through direct or indirect ways.
T67 10800-11027 Sentence denotes Whereas the high mortality and morbidity rates of neurological manifestations, further explorations are needed to develop valid diagnostic and therapeutic approaches, so as to improve the outcome for these patients effectively.
T68 11029-11060 Sentence denotes The article belong to COVID 19.
T69 11061-11077 Sentence denotes Publisher's Note
T70 11078-11196 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T71 11197-11302 Sentence denotes Jianing Wang and Ping Wang contributed equally to this article and should be considered co-first authors.
T72 11304-11320 Sentence denotes Acknowledgements
T73 11321-11421 Sentence denotes This study was supported by Grants from the National Natural Science Foundation of China (81971098).
T74 11423-11430 Sentence denotes Funding
T75 11431-11531 Sentence denotes This study was supported by Grants from the National Natural Science Foundation of China (81971098).
T76 11533-11566 Sentence denotes Compliance with ethical standards
T77 11568-11588 Sentence denotes Conflict of interest
T78 11589-11700 Sentence denotes Jianing Wang, Ping Wang, Chunyi Li, Yihuan Huang, Chunxiao Yang and Lei Zhang declare no conflicts of interest.
T79 11702-11738 Sentence denotes Statement of human and animal rights
T80 11739-11848 Sentence denotes This article does not contain any studies with human participants or animals performed by any of the authors.
T81 11850-11866 Sentence denotes Informed consent
T82 11867-11923 Sentence denotes For this type of study, no informed consent is required.