Neuroinflammation and Its Impact on the Pathogenesis of COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.

Human Brain Organoids as Models for Central Nervous System Viral Infection

“…SARS-CoV-2 is an enveloped, single-stranded RNA virus, belonging to the Coronaviridae family [ 65 ]. Neurological symptoms and sequelae, during or after SARS-CoV-2 infection, have been reported [ 66 , 67 ].…”

“…Neurological symptoms and sequelae, during or after SARS-CoV-2 infection, have been reported [ 66 , 67 ]. Whether SARS-CoV-2 infection causes these complications through direct infection of the CNS or via a SARS-CoV-2-induced immune response is still unclear [ 65 , 68 ]. To investigate if the CNS is susceptible to direct infection, 8 out of 11 studies on SARS-CoV-2 (73%) reported on SARS-CoV-2 receptor expression in the CNS ( Table 1 ).…”

Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms

“…One hypothesis for the brain alteration in SARS-CoV-2 infection is a neuroinflammatory response (6). Our results confirmed a significant association between (i) a decreased GMV and Th in frontal, fronto-orbital, and temporal regions and (ii) increased CSF levels of indirect inflammatory markers (protein, blood/albumin ratio, and EN-RAGE).…”

Possible mechanisms of neuropathies associated with the COVID‐19 vaccines

“…Following administration of the BNT162b2, an mRNA vaccine encoding a P2 mutant spike protein (PS 2) derived from the SARS-CoV-2 spike (S) glycoprotein, the genetic material is expressed, which stimulates an immune response which is very similar to post-viral status, with robust release of immune-modulatory cytokines such as IFNγ, IL-2 and IL-12p70, 5 but also downregulation of TJ proteins as well as increasing some cytokines level, including TNFα, IL-6 and IL-10. 6 TNFα has neurotoxic effects mediated by a rapid impairment of mitochondrial function, 7 while IL-2 and IL-6 could play a neurotoxic role, sometimes associated with demyelinating neuropathies. 8,9 The cytokines activated by SARS-Cov2 protein fragments could also trigger vasculitis in and around nerves.…”

“…8,9 The cytokines activated by SARS-Cov2 protein fragments could also trigger vasculitis in and around nerves. 6 Molecular mimicry through cross-reactivity between epitopes within the COVID-19 spike-bearing gangliosides and some gangliosides containing a disialosyl moiety (GD1b, GQ1b and GT1b) was proposed in patients with neuropathies after COVID-19. 10 Although all these proposed mechanisms could play a role in post-COVID-19 and post-COVID-19 vaccination associated cranial (and peripheral) neuropathies, the relationship remains of probability, especially when there is a plausible timeframe between exposure and clinical event and no other causes were found, but overall these very rare instances do not diminish at all the overwhelming positive benefit-risk ratio of COVID-19 vaccines.…”