Original Article: Steardo, L., Steardo, L., Jr, Zorec, R. and Verkhratsky, A. (2020), Neuroinfection may potentially contribute to pathophysiology and clinical manifestations of COVID‐19. Acta Physiol. Accepted Author Manuscript.
Author of summary: Francesca Di Vozzo; Reviewer: Giulia Poggi
Original Article Published on March 29th, 2020
Coronaviruses are neurotropic; therefore, it is conceivable that also SARS-CoV-2 will show similar tropism. The authors offer a highly speculative description of how SARS-CoV-2 might get access to the nervous system, infect the brainstem nuclei associated with respiratory and cardiovascular regulation, and, consequently, exacerbate or even lead to respiratory failure. Moreover, they hypothesize that systemic inflammation, which accompanies COVID-19, might compromise the blood brain barrier and trigger neuroinflammatory response. This, together with prolonged hypoxia, may result in neuropsychiatric issues and cognitive impairment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19, which was first reported in Wuhan, China in December 2019.
The clinical presentation is mainly manifested as malignant pneumonia, although many patients present neurological symptoms, such as vomiting, dizziness, headache and delirium.
It has been demonstrated that coronaviruses, and especially β-coronaviruses to which the SARS-CoV-2 belongs, do not limit their presence to the respiratory tract and frequently invade the central nervous system (CNS). Coronaviruses may access the CNS through intranasal inoculation and through trans-synaptic pathways from the peripheral nerves. Once they reach the CNS, coronaviruses predominantly infect brain regions responsible for respiratory and cardiovascular regulation. Damage to these areas may lead to respiratory and cardiovascular failure.
Indeed, Angiotensin-Converting Enzyme 2 (ACE2) – the main entry point for SARS-CoV and SARS-CoV-2 infection – is expressed by glia and neurons of the brainstem and of the regions responsible for regulation of cardiovascular function, including subfornical organ, paraventricular nucleus (PVN), nucleus of the tractus solitaries (NTS), and rostral ventrolateral medulla. Importantly, ACE2-independent entry pathways could also contribute to viral infection of neural cells, as it was shown for Tick-borne encephalitis virus (TBEV) and ZIKA virus.
Indirect effects of SARS-CoV-2 on the CNS have also been proposed. SARS-CoV-2, as all the other pathogens, triggers a substantial systemic inflammation that leads to an abundant release of cytokines, chemokines, and other inflammatory components.
Systemic inflammation has been associated with increase permeability of the blood-brain barrier (BBB) and consequent infiltration of peripheral immune milieu into the CNS. This could potentially amplify ongoing neuroinflammatory processes and severely affect brain homeostasis. In a putative model, systemic inflammation and prolonged hypoxia could induce a persistent and uncontrolled neuroinflammatory response. This could impact on the hippocampus and on cortical areas associated with cognitive functions and lead to psychiatric and neurological symptoms. Therefore, neurological and psychiatric aspects of the viral attack must be considered in designing the therapeutic strategies and for rehabilitation paradigms aimed at victims of SARS-CoV-2.