Type I interferon signaling in SARS-CoV-2 associated neurocognitive disorder (SAND): Mapping host-virus interactions to an etiopathogenesis

Abstract

Epidemiological, clinical, and radiological studies have provided insights into the phenomenology and biological basis of cognitive impairment in COVID-19 survivors. Furthermore, its association with biomarkers associated with neuroinflammation and neurodegeneration supports the notion that it is a distinct aspect of LongCOVID syndrome with specific underlying biology. Accounting for the latter, translational studies on SARS-CoV-2's interactions with its hosts have provided evidence on type I interferon dysregulation, which is seen in neuroinflammatory and neurodegenerative diseases. To date, studies attempting to describe this overlap have only described common mechanisms. In this manuscript, we attempt to propose a mechanistic model based on the host-virus interaction hypothesis. We discuss the molecular basis for a SARS-CoV-2-associated neurocognitive disorder (SAND) focusing on specific genes and pathways with potential mechanistic implications, several of which have been predicted by Vavougios and their research group. Furthermore, our hypothesis links translational evidence on interferon-responsive gene perturbations introduced by SARS-CoV-2 and known dysregulated pathways in dementia. Discussion emphasizes the crosstalk between central and peripheral immunity via danger-associated molecular patterns in inducing SAND's emergence in the absence of neuroinfection. Finally, we outline approaches to identifying targets that are both testable and druggable, and could serve in the design of future clinical and translational studies.

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

“…Interestingly, extensive perivascular leukocyte cuffing reportedly occurs only in a subset of COVID-19 decedents, suggesting that individual risk factors contribute to CNS presentation of infection (Agrawal et al, 2022; Thakur et al ., 2021). Individual risk factors related to Cav-1 and other regulators of BBB adhesion and permeability may modify leukocytic infiltration and neurologic symptoms of SARS-CoV-2 infection (Adesse et al, 2022; Iadecola et al, 2020; Monje and Iwasaki, 2022; Teuwen et al, 2020; Vanderheiden and Klein, 2022; Vavougios et al, 2022).…”

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer’s disease

“…Previous works from our group developed a model for the pathogenesis of CNS injury following COVID-19, and the overlap between the mechanisms that mediated with Alzheimer’s disease ( Vavougios et al, 2021b , 2022a , b , c ). We built this model upon in silico evidence of overlapping immune pathway dysregulation between peripheral blood and central nervous system sites in Alzheimer’s disease patients ( Vavougios et al, 2020 ).…”

“…This transmission would require the interface between a peripheral site (e.g., the olfactory neuroepithelium, the brain vascular endothelium; Vavougios et al, 2022c ) and a central site (such as the hippocampus) ( Vavougios et al, 2021b ). While peripheral stimulation persists, central sites would be exposed to prolonged IFN-I signaling and proinflammatory conditions which would be deleterious to neurogenesis, synaptogenesis and by extent, cognition ( Vavougios et al, 2022a , b ; Crook et al, 2023 ). Once IFN-I signaling has been localized to the CNS, it may become feed-forward due to the production of (DAMPs), a concept displayed experimentally in Alzheimer’s disease ( Roy et al, 2020 , 2022 ) with therapeutic implications for targeting both microglial responses and IFN-I ( Moore et al, 2020 ).…”

“…We proposed that similar molecular mechanisms overlap between Alzheimer’s disease (AD) and COVID-19, with a focus on Type I interferon signaling (IFN-I) ( Vavougios et al, 2022a ). There are several reasons why IFN-I may account for the effects of COVID-19 on the CNS, and their overlap with Alzheimer’s disease pathogenesis.…”

“…In COVID-19, type I interferon signaling is a primary innate immune response against SARS-CoV-2 that has been shown to be dysregulated as a result of complex host-response interactions ( Lee and Shin, 2020 ; Shi et al, 2021 ; Eskandarian Boroujeni et al, 2022 ; Wu et al, 2022 ). Dysregulated type I interferon signaling has been shown to extend to sites proximal to the CNS, such as the olfactory bulb, the choroid plexus, and brain endothelial cells (reviewed in Vavougios et al, 2022a ; Crook et al, 2023 ). Within the context of the studies presented, this peripheral activation of IFN-I due to COVID-19 can affect the CNS with a predilection for neurogenesis sites such as the hippocampus and the olfactory bulb ( Ekdahl et al, 2003 ; Baruch et al, 2014 ; Bayat et al, 2022 ; Stępień et al, 2023 ), correspondingly mediate cognitive impairment ( Blank et al, 2016 ) and anosmia ( Llana et al, 2022 , 2023 ).…”