Neuroimmune multi-hit perspective of coronaviral infection

Abstract

It is well accepted that environmental stressors experienced over a one’s life, from microbial infections to chemical toxicants to even psychological stressors, ultimately shape central nervous system (CNS) functioning but can also contribute to its eventual breakdown. The severity, timing and type of such environmental “hits”, woven together with genetic factors, likely determine what CNS outcomes become apparent. This focused review assesses the current COVID-19 pandemic through the lens of a multi-hit framework and disuses how the SARS-COV-2 virus (causative agent) might impact the brain and potentially interact with other environmental insults. What the long-term consequences of SAR2 COV-2 upon neuronal processes is yet unclear, but emerging evidence is suggesting the possibility of microglial or other inflammatory factors as potentially contributing to neurodegenerative illnesses. Finally, it is critical to consider the impact of the virus in the context of the substantial psychosocial stress that has been associated with the global pandemic. Indeed, the loneliness, fear to the future and loss of social support alone has exerted a massive impact upon individuals, especially the vulnerable very young and the elderly. The substantial upswing in depression, anxiety and eating disorders is evidence of this and in the years to come, this might be matched by a similar spike in dementia, as well as motor and cognitive neurodegenerative diseases.

SARS-CoV-2 and neurodegenerative diseases: what we know and what we don’t

“…Mild encephalopathies with transient symptoms such as altered consciousness (19.1% of 841 patients) or bradypsychia and disorientation (10.1% of 841 patients) were found to occur rather commonly often accompanied by findings of unspecific T2/FLAIR hyperintensity (35% of 20 patients) and ischemic infarcts (31% of 108 patients) in neuroimaging (Romero-Sanchez et al 2020 ; Mahammedi et al 2020 ; Radmanesh et al 2020 ). Severe COVID-19-associated encephalopathies including ADEM or acute necrotizing encephalopathies and poly(radiculo)neuropathies as GBS or other acute neuropathies (multifocal demyelinating or small fiber polyneuropathy) have also been described in several case reports with an estimated prevalence of 0.1–1% in western countries within 6 weeks of confirmed infection (Mahapure et al 2021 ; Parsons et al 2020 ; Shahali et al 2021 ; Toscano et al 2020 ; Camdessanche et al 2020 ; Hayley and Sun 2021 ; Dixon et al 2020 ; Poyiadji et al 2020 ; Oaklander et al 2022 ). For some entities, a causative relationship to prior SARS-CoV-2 infection is less clear.…”

Anorexia nervosa and autoimmune comorbidities: A bidirectional route?

“…Curiously, some psychiatric disorders have been linked to excessive activation of the immune system (IS). The release of soluble inflammatory mediators and the mobilization of immune cells can also be stimulated by adequate psychological stressors 12 . Both functional and structural brain alterations 13 such as brain volume loss, astrocyte reduction, and inflammation 14 are commonly related to AN.…”

“…It is intuitive that the brain and the IS are the ones mainly responsible for regulating relations with the external environment and have evolved together with the aim of preserving the internal homeostasis of the organism. Therefore, these are systems strictly interconnected in a bidirectional way allowing a balanced and safe relationship of the organism with the environment 12 . AN is associated with a mild inflammatory state, alterations in the immune response, the production of autoantibodies, and occurs during autoimmune diseases, but this is also true in the opposite sense: those affected by autoimmune disorders present similar pathophysiological conditions and can develop anorexia.…”

“…The release of soluble inflammatory mediators and the mobilization of immune cells can also be stimulated by adequate psychological stressors. 12 Both functional and structural brain alterations 13 such as brain volume loss, astrocyte reduction, and inflammation 14 are commonly related to AN. We have a lot of evidence of how the IS, along with neurochemical and hormonal responses, can significantly influence central nervous system (CNS) stress circuitry, especially through inflammation molecules.…”

“…Therefore, these are systems strictly interconnected in a bidirectional way allowing a balanced and safe relationship of the organism with the environment. 12 AN is associated with a mild inflammatory state, alterations in the immune response, the production of autoantibodies, and occurs during autoimmune diseases, but this is also true in the opposite sense: those affected by autoimmune disorders present similar pathophysiological conditions and can develop anorexia. The aim of our work is to bring together the current knowledge on the neuroimmune interaction in AN with new interesting therapeutic perspectives as opened up by the hypothesis of autoimmune mechanisms.…”