In this theoretical article, the authors from the United Arab Emirates and Australia discuss the possible pathways and mechanisms of SARS-CoV-2 neuroinvasion, focusing on the role of the hypothalamic circuits in the SARS-CoV-2 infection of the central nervous system (CNS), and their possible involvement in the neurological manifestations of COVID-19.
A significant number of individuals with COVID-19 or the postacute phase of COVID-19 exhibit neurological symptoms, which are classified as the CNS symptoms, such as anosmia, dizziness, headache, stroke, cognitive and memory disorders, extrapyramidal and movement disorders, mental disorders, encephalitis or encephalopathy, and the peripheral nervous system (PNS) symptoms, like sensory disorders, polyneuropathy, orthostatic intolerance and syncope. The rise in the number of patients with neurological manifestations underscores the importance of identifying the mechanisms of the CNS infection and the regions within the CNS implicated in the pathogenesis of neuroCOVID.
The hypothalamus is a complex structure located within the ventral part of the diencephalon at the base of the brain. It is composed of numerous cell groups and neuronal circuits that are strongly interconnected. Aside from complex intrahypothalamic connections, the hypothalamus also projects to different regions within the brain, forming large neuronal networks. The hypothalamic nuclei are involved in the regulation of a diverse range of physiological functions including respiration, the integration of stress responses, thermoregulation, cardiovascular regulation, glycaemia, neuroendocrine regulation, and consciousness.
One of the main responses of the hypothalamus to various homeostatic challenges is the stress response. It has been suggested that both SARS-CoV and SARS-CoV-2 are capable to alter the stress response and, consequently, cortisol dynamics. The autopsies of individuals infected with SARS-CoV have revealed the degeneration and necrosis of the adrenal cortical cells. The findings of hypocortisolism and low levels of dehydroepiandrosterone sulfate found in patients infected with SARS-CoV-2, indicate damage to the hypothalamic–pituitary circuits. Also, the impaired function of neurons secreting gonadotropin-releasing hormone may lead to low testosterone levels, or hypogonadotropic hypogonadism in patients with COVID-19 or long COVID. https://discovermednews.com/hypotestosteronemia-men-covid-19-post-covid-hypothalamic-origin/
Viral entry into the CNS
In the introduction to this article, the authors discussed different pathways for viral entry into the CNS. The neuroinvasion by CoVs has been documented for almost all the β-CoVs, including SARS-CoV, MERS-CoV, and SARS-CoV-2, resulting in a similar spectrum of symptoms. The viruses enter the CNS via different pathways. The proposed pathways include the blood brain barrier (BBB), cerebrospinal fluid (CSF) barrier, and retrograde axonal transport. The utilization of infected hematopoietic cells as “Trojan horses” is another hematogenic pathway by which viruses enter the CNS. The viruses mainly enter the CNS via peripheral sensory nerves or dendrites of olfactory sensory neurons, but, can also use the olfactory pathway and the hematogenic pathway simultaneously.
The BBB and blood-CSF barrier are highly complex networks that protect the CNS parenchyma from harmful elements, including viruses. Certain viruses are capable of overcoming these obstacles by infecting vascular endothelial cells, facilitating the direct passage of viruses through these barriers to the CNS. The CSF as a major transportation route for SARS-CoV-2 has been questioned, given that clinical studies failed to detect significant levels of viral RNA in the CSF. Importantly, some CNS structures, like the choroid plexus and the circumventricular organs including the hypothalamus, are not completely protected by the BBB and can serve as virus entry points. The breakdown of the BBB and blood-CSF barrier, induced by inflammation due to systemic viral infection, facilitates the passages of viruses through the fenestrations into the CNS.
The significance of hypothalamic–olfactory system crosstalk for viral infection
It is believed that the olfactory bulb is the main gateway for viral entry into the brain. Studies conducted on transgenic mice for the SARS-CoV receptor ACE2 have demonstrated that the olfactory bulb serves as the site of viral entry into the CNS after intranasal inoculation. The viral antigens were then detected in other regions of the CNS that possess first- or second-order neural connections with the olfactory bulb, such as the cerebral cortex, basal ganglia, the midbrain, and the hypothalamus.
As a relay station, the hypothalamus communicates with almost all regions of the brain, especially the brainstem, upon receiving extensive peripheral sensory inputs from diverse sources, including the olfactory system. The hypothalamus has complex anatomical and functional connections with the olfactory bulb. It has been shown that four areas in the posterior lateral hypothalamus (anterior olfactory nucleus, olfactory tubercle, piriform cortex, and anterior cortical nucleus of amygdala) receive the input from the olfactory bulb. Several neuropeptides, including gonadotropin-releasing hormone, neuropeptide Y, leptin, adiponectin, and orexins, are involved in the modulation of connections between the hypothalamus and the olfactory bulb. According to the authors, the olfactory system plays a crucial role in the transport of SARS-CoV-2 into the CNS via the hypothalamus.
The role of hypothalamic circuits in the viral infection
Certain CNS structures, such as the choroid plexus and the circumventricular organs including the hypothalamus, are not completely protected by the BBB and can serve as virus entry points. In the circumventricular organs, the brain endothelium is fenestrated. The median eminence of the hypothalamus is one such circumventricular organ. It is located in the basal hypothalamus, ventral to the third ventricle and adjacent to the arcuate nucleus. The median eminence contains a rich capillary plexus, a fenestrated endothelium, and tanycytes, which form the specialized ependymoglial cellular sheet that covers the floor and the basolateral walls of the third ventricle. It has been hypothesized that one of the functions of these cells is to create a barrier that prevents substances in the portal capillary spaces from entering the brain.
However, the unique structure of the BBB at the median eminence/arcuate nucleus interface has a major role in the exposure of hypothalamic neurons to systemic factors, including viruses. The results of an immunocytochemistry study, which examined the distribution of tight junction proteins in the cells that line the ventricular wall of the third ventricle in the tuberal region of the hypothalamus, revealed a differential pattern of tight junction protein expression in different locations. The tanycytes of the median eminence were joined at their apices by functional tight junctions. This finding was consistent with their role in regulation of blood-hypothalamus exchange by forming a cellular sheet that is impermeable to blood-borne molecules at the floor of the third ventricle. In contrast, the arcuate tanycytes created a permeable layer that allowed unrestrained diffusion of molecules between the CSF and compartments of the arcuate nucleus. This finding confirmed the role of the median eminence/arcuate nucleus interface in the exposure of hypothalamic neurons to systemic factors, including viruses. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892518/
The authors concluded that hypothalamic circuits play a central role in the majority of neurological symptoms associated with COVID-19. They pointed out the importance of the hypothalamic circuits in the SARS-CoV and SARS-CoV-2 infections. Further investigation is required to identify the precise hypothalamic circuits that serve as an entry point for the viruses, and contribute to the neurologic manifestations associated with COVID-19.
This article was published in Viruses
Journal Reference
Mussa, B.M, Srivastava, A., Verberne, AJM. COVID-19 and Neurological Impairment: Hypothalamic Circuits and Beyond. Viruses 2021, 13, 498. (Open Access) https://doi.org/10.3390/v13030498
