Abstract
At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in China, causing a new coronavirus disease, termed COVID-19 by the WHO on February 11, 2020. At the time of this paper (January 31, 2021), more than 100 million cases have been recorded, which have claimed over 2 million lives worldwide. The most important clinical presentation of COVID-19 is severe pneumonia; however, many patients present various neurological symptoms, ranging from loss of olfaction, nausea, dizziness, and headache to encephalopathy and stroke, with a high prevalence of inflammatory central nervous system (CNS) syndromes. SARS-CoV-2 may also target the respiratory center in the brainstem and cause silent hypoxemia. However, the neurotropic mechanism(s) by which SARS-CoV-2 affects the CNS remain(s) unclear. In this paper, we first address the involvement of astrocytes in COVID-19 and then elucidate the present knowledge on SARS-CoV-2 as a neurotropic virus as well as several other neurotropic flaviviruses (with a particular emphasis on the West Nile virus, tick-borne encephalitis virus, and Zika virus) to highlight the neurotropic mechanisms that target astroglial cells in the CNS. These key homeostasis-providing cells in the CNS exhibit many functions that act as a favorable milieu for virus replication and possibly a favorable environment for SARS-CoV-2 as well. The role of astrocytes in COVID-19 pathology, related to aging and neurodegenerative disorders, and environmental factors, is discussed. Understanding these mechanisms is key to better understanding the pathophysiology of COVID-19 and for developing new strategies to mitigate the neurotropic manifestations of COVID-19.
Highlights
Human coronaviruses (CoVs) were first identified in the mid-1960s and were named for the crownlike spikes on their surface (Figure 1A)
A clear difference in neurovirulent properties was documented between the 93/783 and Torö strains (Lindqvist et al, 2020). These two strains exhibit differences in their E protein properties, which result in enhanced binding and host cell entry of the more virulent strain 93/783. These effects were evident in neurons, while in astrocytes, no differences were noted between both strains in their host cell entry efficacy, but only in their replication rate
In analogy with neurotropic flavivirus strains, it is expected that different SARS-CoV-2 strains may trigger somewhat different neurological symptoms as well as variations in the response to different vaccines
Summary
Human coronaviruses (CoVs) were first identified in the mid-1960s and were named for the crownlike spikes on their surface (Figure 1A). Astrocytes provide a favorable environment to support replication of viruses, since they exhibit aerobic glycolysis This special adaptation of metabolism exists in rapidly dividing cells and in cells undergoing plastic morphological changes, despite the presence of adequate levels of oxygen, a phenomenon known as “the Warburg effect” (Vander Heiden et al, 2009), typically present in cancer cells. While this form of metabolism is not very efficient in producing ATP, it is the biosynthetic intermediates of this metabolism, that provide an essential advantage for cells in developing and growing tissues (Tech and Gershon, 2015) supporting the replication of viruses (Zorec et al, 2019). Neuroinfection may contribute to the pathophysiology of COVID-19 through impaired astroglial function
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