SARS-CoV-2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

Abstract

With confirmed COVID-19 cases surpassing the 8.5 million mark around the globe, there is an imperative need to deepen the efforts from the international scientific community to gain comprehensive understanding of SARS-CoV-2. Although the main clinical manifestations are associated with respiratory or intestinal symptoms, reports of specific and non-specific neurological signs and symptoms, both at presentation or during the course of the acute phase, are increasing. Approximately 25-40% of the patients present neurological symptoms. The etiology of these neurological manifestations remains obscure, and probably involves several direct pathways, not excluding the direct entry of the virus to the Central Nervous System (CNS) through the olfactory epithelium, circumventricular organs, or disrupted blood-brain barrier (BBB). Furthermore, neuroinflammation might occur in response to the strong systemic cytokine storm described for COVID-19, or due to dysregulation of the CNS angiotensin system. Descriptions of neurological manifestations in patients in the previous coronavirus (CoV) outbreaks have been numerous for the SARS-CoV and lesser for MERS-CoV. Strong evidence from patients and experimental models suggests that some human variants of CoV have the ability to reach the CNS and that neurons, astrocytes and/or microglia can be target cells for CoV. A growing body of evidence shows that astrocytes and microglia have a major role in neuroinflammation, responding to local CNS inflammation and/or to dysbalanced peripheral inflammation. This is another potential mechanism for SARS-CoV-2 damage to the CNS. In this work we will summarize the known neurological manifestations of SARS-CoV-2, SARS-CoV and MERS-CoV, explore the potential role for astrocytes and microglia in the infection and neuroinflammation, and compare them with the previously described human and animal CoV that showed neurotropism. We also propose possible underlying mechanisms by focusing on our knowledge of glia, neurons, and their dynamic intricate communication with the immune system.

3D Bioprinted Neural‐Like Tissue as a Platform to Study Neurotropism of Mouse‐Adapted SARS‐CoV‐2

“…Infection of 2D cultures indicates that both cell types could potentially be used by the virus to infect the CNS, through ACE2/TMRPSS2 and ACE2/neuropilin-1 routes, contributing to virus spread in the brain. [77,78] Results of immunostaining suggest that astrocytes present higher susceptibility to infection than neurons, with quantification of immunofluorescence for spike + cells over DAPI showing that 15.7 ± 2.9% of astrocytes were infected by MA-SARS-CoV-2, while for neurons, this value corresponded to 10.3 ± 2.1% (Figure S6A, Supporting Information). Similarly, Jacob et al reported the ability of hSARS-CoV-2 to preferentially infect 2D culture of human primary astrocytes as compared to neurons, being observed sparse infection after 48 h. [64] Astrocytes also showed a significantly higher capacity to replicate the mouse-adapted virus than neurons, being analyzed 48 hpi.…”

“…[80,81] In face of an injury, including viral infection, [82][83][84] astrocytes respond with reactivity, a mechanism that leads to the production of several inflammatory cytokines. [77] In order to evaluate the regulation of inflammation mediators by astrocytes after MA-SARS-CoV-2 infection, we characterized the expression of the inflammatory cytokines IL1-β and TNF-α, in addition to the expression of the chemokine CXCL12 and its receptor CXCR4. Results showed that MA-SARS-CoV-2 infection upregulated the expression of CXCL12 and CXCR4, while the inflammatory cytokines were downregulated in the infected astrocytes condition (Figure 4C).…”

The Impact of the COVID-19 Pandemic on Dementia Risk: Potential Pathways to Cognitive Decline

“…While these human and animal findings provide evidence that part of the neuroinflammation could be directly occurring from SARS-CoV-2 neurotropism, systemic inflammation may also influence the immune signaling of astrocytes and microglia. In particular, mere exposure to proinflammatory cytokines, expressed from the periphery, could increase the permeability of the BBB (increasing likelihood of direct viral infection) as well as influence astrocytes in such a way to induce neurodegeneration and further neuroinflammation [100]. Therefore, the generation, quantity, and type of periphery proinflammatory cytokines play an important role in neurodegeneration [98].…”

“…Therefore, the generation, quantity, and type of periphery proinflammatory cytokines play an important role in neurodegeneration [98]. Regardless of whether SARS-CoV-2 directly uses astrocytes as viral hosts or influences them from indirect periphery signals, there are multiple pathways to acute neurovirulence that need to be further researched to understand exactly how the brain is affected [100].…”

A Cytokine-based model for the pathophysiology of Long COVID symptoms

“…In summary, a peripheral inflammatory response may lead to cytokine release and mobilization of immune cells, both of which have CNS effects [153,167] . SARS-CoV-2 can affect the CNS via proinflammatory cytokines, producing neurological symptoms [167] . Such "sickness behavior" usually resolves once the acute illness terminates.…”