Neuroimmune correlates of the nervous system involvement of COVID-19: A commentary.

Dear editor,

We recently read with interest the article by Sedaghat and Karimi entitled “Guillain Barre syndrome associated with COVID-19 infection: A case report” [1]. Strikingly, they postulated that enhanced inflammatory signalling and immune-mediated processes which are activated by SARS-CoV-2 might imitate the molecular architecture of self-directed immunity in the peripheral nervous system and might lead to Guillain Barre syndrome (GBS), an autoimmune disorder. Additionally, patients with febrile seizures, convulsions, changes in mental state and encephalitis have been reported due to SARS‐CoV‐2 and other human coronaviruses [2], [3]. Concerning these interesting reports, herein, we would like to identify possible mechanisms through which SARS-CoV-2 involved in both the peripheral nervous system (PNS) and central nervous system (CNS).

Troyer and colleagues have suggested that the main pathophysiology of SARS-CoV-2-associated encephalitis may be SARS-CoV-2-induced immunologic response that causes inflammatory damage in the CNS, rather than the infiltration of the virus itself [4]. From this perspective, neurodegeneration might be as a result of angiotensin-converting enzyme-2 (ACE2) receptor-associated high cytokine levels in the brain. CoV binds to ACE2 receptors, which are found in glia and neurons, causing high levels of TNF-alpha, IL-1, IL-6 secretion, and it is suggested that neuropsychiatric symptoms may occur because of such a proinflammatory response in the CNS [5]. Another possible pathophysiological mechanism is that CoV infects peripheral myeloid cells and is transmigrated the blood–brain barrier via peripheral immune cells. In the CNS, virus-infected immune cells may promote the microglial activation, stimulate the release of proinflammatory cytokines, and propagate neuroinflammation, which may directly involve in the emergence of neuropsychiatric symptoms [6]. Moreover, these peripheral myeloid cells infected by CoV may induce autoimmune mechanisms and lead autoimmune disorders. Such as multiple sclerosis (MS), GBS and Bickerstaff Brainstem encephalitis (BBE), being autoimmune disorders of the nervous system that caused by SARS-CoV-1 and MERS-CoV, have been reported [7], [8], [9], while Sedaghat and Karimi reported the first patient with SARS-CoV-2-associated GBS [1]. Remarkably, effective treatment would be warranted when the occurrence of such the autoimmune syndromes is demonstrated to be associated with CoV infection.

On the other hand, CoV infection might involve in both the PNS and CNS directly. Although human coronaviruses primarily target the human respiratory system, they also have neuroinvasive capabilities and can transmit from the respiratory tract to the CNS [10]. CoV causes neuronal death following the penetrance to the CNS [11], which is previously confirmed by rodent models [5]. It has been suggested that CoV not only possess neurotropic characteristics but also they tend to persist in the CNS despite being treated or remained asymptomatic. Accordingly, in a rodent model, RNA of HCoV-OC43 have been isolated in the CNS of infected mice in the first year of the treatment [12]. In a post-mortem analysis, human coronavirus RNA was presented in 48% of a donor group consisted of individuals with neurological disorders and healthy subjects [7]. Furthermore, unlike other CoV species, SARS-CoV-2 is thought to infiltrate to subcortical structures including nuclei which operate as respiratory control centres in the pons and medulla, leading to severe respiratory distress [13]. These findings suggest that a human respiratory pathogen which may directly infect and be latent in the human CNS might involve in severe and irreversible nervous and respiratory system pathologies.

It should be considered that neuropsychiatric manifestations related to human coronaviruses including SARS-CoV-2 might be associated with the involvement of both neuroimmune response and direct viral transmission. Because CoV are tend to persist in the CNS, long-term follow-up and neuropsychiatric monitoring should be performed in patients with COVID-19. We believe that psychoneuroimmunological aspects of COVID-19 should be of great research interest.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.