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Neuroinflammation leads to Encephalitis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of Sars-CoV-2 spike protein to ACE 2 receptors expressed on brain cells (neuronal and non-neuronal) leads to neuroinflammation resulting in encephalitis||adjacent||High||Low||Agnes Aggy (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Coronavirus infection can infect macrophages, microglia, and astrocytes in the CNS leading to encephalitis (Wu et al. 2020; Wu and Tang. 2020) (Koralnik et al. 2020).
Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin). In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis (Pilotto A et al. 2021).
Evidence Supporting this KER
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Koralnik et al. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020 Jul;88(1):1-11.
Pilotto A et al. SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses. Clin Infect Dis. 2021 Jan 4;ciaa1933.
Wu J. and Tang Y. Revisiting the Immune Balance Theory: A Neurological Insight Into the Epidemic of COVID-19 and Its Alike. Front Neurol. 2020 Oct 15;11:566680.
Wu Y, et al. Nervous system involvement after infection with Covid-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22.