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Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders? - PubMed

Review

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

Veronica Murta et al. ASN Neuro. 2020 Jan-Dec.

Abstract

With confirmed coronavirus disease 2019 (COVID-19) cases surpassing the 18 million mark around the globe, there is an imperative need to gain comprehensive understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are associated with respiratory or intestinal symptoms, reports of neurological signs and symptoms are increasing. 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. Furthermore, neuroinflammation might occur in response to the strong systemic cytokine storm described for COVID-19, or due to dysregulation of the CNS rennin-angiotensin system. Descriptions of neurological manifestations in patients in the previous coronavirus (CoV) outbreaks have been numerous for the SARS-CoV and lesser for Middle East respiratory syndrome coronavirus (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 disbalanced peripheral inflammation. This is another potential mechanism for SARS-CoV-2 damage to the CNS. In this comprehensive review, 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 to propose possible underlying mechanisms.

Keywords: COVID-19; MERS; SARS; central nervous system; coronavirus; glia.

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Figures

Figure 1.
Figure 1.

SARS-CoV-2 Potential Entry Routes to the CNS. SARS-CoV-2 may reach CNS using two main routes: the olfactory epithelium or the hematogenous (blood) routes. When entering through the olfactory epithelium, viral particles would have access to the CNS using transneuronal/synaptic pathways. Following neuronal infection, viral particles released may infect microglia and astrocytes. In the hematogenous entry route, endothelial cells may become infected, followed by perivascular astrocytes and perivascular macrophages. Secondarily, viral particles may reach microglia and neurons. Also during viremia in severe affected patients, SARS-CoV-2 can reach choroid plexus and circumventricular organs, which lack of BBB, and subsequently entering to brain parenchyma. A third possibility of CNS infection may arise after BBB breakdown as a consequence of systemic inflammation and cytokine release. Increased BBB permeability could facilitate SARS-CoV-2 entrance to the CNS. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; CNS = central nervous system; CSF = cerebrospinal fluid; BBB = blood–brain barrier.

Figure 2.
Figure 2.

Potential Astroglial and Microglial Roles in SARS-CoV-2 Infection. Astrocytes and microglia are viral hosts: Perivascular astrocytes may incorporate viral particles by direct contact with infected endothelial cells. However, BBB breakdown may also lead to viral infection of nonperivascular astrocytes and microglia. In both situations, infected cells may act as viral hosts giving nonproductive infection with mild inflammatory response and with microglia acting as antigen-presenting cells; or astrocytes may give rise to a productive infection, with destruction of astroglial network. This latter possibility is more unlikely based on clinical findings. Astrocytes and microglia are not viral hosts: Astrocytes and microglia are not primary targets of viral infection, but they are responsive to proinflammatory signals from endothelial cells, macrophages, and/or neurons. In such case, astrocytes and microglia may engage in a proinflammatory gene expression program that would expand neuroinflammation. This maladaptive reactive astrogliosis would reduce neuroprotective and metabolic support to neurons which secondarily may degenerate by lack of nutrients and neurotrophic factors. A = astrocytes; M = microglia; N = neurons.

Figure 3.
Figure 3.

Microglia and Astrocytes as Effectors of Altered Brain RAS. RAS-mediated proinflammatory priming: SARS-CoV-2 utilizes ACE2 as an entry route and reduces ACE2 availability and activity in endothelial cells. Reduced ACE2 activity increases Ang II levels and consequently ATR1 activity in microglial cells that respond with activation of NF-κB and proinflammatory gene expression. Astrocytes respond to proinflammatory microglial mediators expanding neuroinflammation and neurodegeneration. Reduced anti-inflammatory and antioxidant activity: Decreased ACE2 activity reduces Ang (1-7) concentration and MasR activity in astrocytes and other cell types. Reactive oxygen species and proinflammatory mediators increase in CNS parenchyma and also in brain blood vessels. Neuronal malfunction or even neuronal death may occur in this situation. A = astrocytes; M = microglia; N = neurons.

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References

    1. Abbasi Pashaki P., Habibi Roudkenar M., Rahim F., Ebrahimi A. (2020). From SARS-CoV to SARS-CoV2: A potential guide to better understanding of pathophysiology of the disease and potential therapeutic modality. Eur Rev Med Pharmacol Sci, 24, 7816–7825. - PubMed
    1. Abiodun O. A., Ola M. S. (2020). Role of brain renin angiotensin system in neurodegeneration: An update. Saudi J Biol Sci, 27, 905–912. - PMC - PubMed
    1. Agrawal A. S., Garron T., Tao X., Peng B.-H., Wakamiya M., Chan T.-S., Couch R. B., Tseng C.-T. K. (2015). Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol, 89, 3659–3670. - PMC - PubMed
    1. Alam S. B., Willows S., Kulka M., Sandhu J. K. (2020). Severe acute respiratory syndrome coronavirus-2 may be an underappreciated pathogen of the central nervous system. Eur J Neurol Advance online publication. 10.1111/ene.14442 - DOI - PMC - PubMed
    1. Algahtani H., Subahi A., Shirah B. (2016). Neurological complications of Middle East respiratory syndrome coronavirus: A report of two cases and review of the literature. Case Rep Neurol Med, 2016, 3502683. - PMC - PubMed

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