The two pronged approach: The direct and indirect mechanisms mediating SARS-CoV-2 effects on the central nervous system

Abstract

Neurological symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported in addition to primarily respiratory symptoms. These symptoms range from mild chronic effects including headaches and fatigue to acute consequences including stroke and encephalitis. Although a crucial field of research, mechanisms as to how SARS-CoV-2 exerts these effects remains unclear. However there is growing evidence to suggest underlying mechanisms are likely multifactorial. Thus examining the impact of SARS-CoV-2 on the central nervous system (CNS) is key because of its wide array of noted neurological effects, vexing underlying mechanisms and its potential relationship with long-COVID. Assessing leading hypotheses for proposed mechanisms by which SARS-COV-2 mediates neurological symptoms is an emerging field. This article will examine the effects and support for potential mechanisms of SARS-CoV-2 direct neuroinvasion of the CNS. We will also explore the effects and support for means by which SARS-CoV-2 can indirectly contribute to neurological symptoms without the virus entering the CNS, through the host response. Examining this field provides context in understanding neurological effects alongside their contributing viral and host mechanisms to assess neurological impact and develop potential remedies for both acute and chronic symptoms. This article found direct mechanisms of neuroinvasion of SARS-CoV-2 include transversal of the blood brain barrier (BBB) by means of endothelial cells and astrocytes as well as passage through the olfactory pathway. Indirect effects on the CNS mediated by the host’s response consist of excessive neuroinflammation and hypoxic damage to brain tissue. The impact of this work in characterizing CNS effects and underlying mechanisms strengthens the foundation and provides new avenues for which areas, cells, and processes could be used to develop novel diagnostics and therapeutics. The emergence of SARS-CoV-2 variants of concern (VoC) also pose a concern for neurological impacts, emphasizing our need to advance this field.