SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism

Abstract

The recent outbreak of SARS-CoV-2 infections that causes coronavirus-induced disease of 2019 (COVID-19) is the defining and unprecedented global health crisis of our time in both the scale and magnitude. Although the respiratory tract is the primary target of SARS-CoV-2, accumulating evidence suggests that the virus may also invade both the central nervous system (CNS) and the peripheral nervous system (PNS) leading to numerous neurological issues including some serious complications such as seizures, encephalitis, and loss of consciousness. Here, we present a comprehensive review of the currently known role of SARS-CoV-2 and identify all the neurological problems reported among the COVID-19 case reports throughout the world. The virus might gain entry into the CNS either through the trans-synaptic route via the olfactory neurons or through the damaged endothelium in the brain microvasculature using the ACE2 receptor potentiated by neuropilin-1 (NRP-1). The most critical of all symptoms appear to be the spontaneous loss of breathing in some COVID-19 patients. This might be indicative of a dysfunction within the cardiopulmonary regulatory centers in the brainstem. These pioneering studies, thus, lay a strong foundation for more in-depth basic and clinical research required to confirm the role of SARS-CoV-2 infection in neurodegeneration of critical brain regulatory centers.

Keywords: ACE1; ACE2; Brain; COVID-19; Coronavirus; Headache; Loss of consciousness; Loss of smell; Loss of taste; Nervous system; Neuropilin-1; SARS-CoV-2; Seizures; Stroke.

Fig. 1

Potential routes of SARS-CoV-2 entry into the brain. (A) Loss of smell sensation in many of the COVID-19 patients as one of the initial sy65mptoms suggests that the most likely route of viral entry to the brain may be through the olfactory epithelial cells, which abundantly express ACE2, followed by transmission to the olfactory bulb and higher brain regions through trans-synaptic transfer. This mechanism bypasses the BBB. (B) Viral entry through the brain capillary endothelial cells is also likely as they too express very high levels of ACE2. Once endothelial cells are damaged by viral overproduction, the virus can sneak through the underlying smooth muscle cells and finally to astrocytes, microglia, and neurons which also express ACE2. (C) The identification of viral particles in the ocular fluid in some COVID-19 patients also indicates SARS-CoV-2 can infect eyes and through the optic nerve may reach the occipital cortex and other areas of the brain including the brainstem

Fig. 2

SARS-CoV-2-mediated neurodegeneration may be due to the downregulation of ACE2-mediated signaling and concomitant increase in ACE1-mediated neuroinflammation. SARS-CoV-2 binds ACE2 through the receptor-binding domain (RBD) of spike protein S1 facilitated by protease TMPRSS2, resulting in reduced functional ACE2 expression which in turn enhances ACE1 signaling including increased conversion of angiotensin I to angiotensin II. ACE2 is responsible for the conversion of angiotensin I into angiotensin 1-9 which increases nitric oxide (NO) generation and vasodilation. With reduced ACE2, angiotensin 1-9 levels are reduced and therefore NO generation is also reduced. ACE2 is also responsible for the conversion of angiotensin II into angiotensin 1-7 which enhances Mas receptor (MasR) signaling to increase vasodilation and to prevent fibrosis. With the reduction in ACE2, MasR signaling is also reduced. Increased angiotensin II levels due to decreased ACE2 activity can also enhance signaling through the type-1a (AT₁R) or type-2 (AT₂R) angiotensin receptors. Activation of AT₂R is normally neuroprotective. However, increased AT₁R signaling leads to reduced NO generation, and therefore vasoconstriction, AT₁R signaling also increases oxidative stress and neuroinflammation with the overproduction of interleukins such as IL-1, IL-6, IL-8, and IL-29, all of which were confirmed in COVID-19 patients. Increased neuroinflammation in turn can cause neurodegeneration, brain dysfunction, and a variety of neurological issues as seen among COVID-19 patients. A schematic representation of a signal transduction mechanism is shown for endothelial cells of brain capillaries, and a similar mechanism is also expected in neurons and glia which also has been shown to express ACE2