SARS-CoV-2 and type I interferon signaling in brain endothelial cells: Blurring the lines between friend or foe

Vavougios, George D.; Zarogiannis, Sotirios G.; Hadjigeorgiou, Georgios M.; Krogfelt, Karen A.; Gourgoulianis, Konstantinos

doi:10.1016/j.stemcr.2022.04.011

Cited by 4 publications

(8 citation statements)

References 11 publications

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“…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 ).…”

Section: Tonic Type I Interferon Signaling Dysregulation As a Shared ...mentioning

confidence: 99%

“…Quasi-infectious here is used to describe the initial stimulation of IFN-I signaling by a pathogen, and the subsequent sterile elicitation of IFN-I activation centrally by endogenous disease associated molecular patterns (DAMPs). 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 ).…”

Section: Tonic Type I Interferon Signaling Dysregulation As a Shared ...mentioning

confidence: 99%

“…The generation of amyloid-beta and hyperphosphorylated tau, molecules that we currently recognize as inducers of innate immunity ( Rexach et al, 2020 ; Roy et al, 2020 ; Jin et al, 2021 ; Roy et al, 2022 ; Vavougios et al, 2022a ; Udeochu et al, 2023 ), can in turn sustain pathogenic IFN-I in a feed-forward manner acting as danger associated molecular pattern ( Asai et al, 2015 ; Bolós et al, 2016 ) in a process that has been shown to prime microglia towards phenotypes specifically associated with the earlier stages of neurodegenerative disease ( Roy et al, 2020 ; Jin et al, 2021 ; Magusali et al, 2021 ; Kim et al, 2022 ; Udeochu et al, 2023 ). This aspect of our model, previously predicting beta amyloidosis and tauopathy based on the IFN-I response secondary to SARS-CoV-2 infection ( Ramani et al, 2020 ; Vavougios et al, 2021a , b , 2022a , b , c ; Di Primio et al, 2023 ) has been independently validated ( Ramani et al, 2020 ; Green et al, 2022 ; Käufer et al, 2022 ; Ma et al, 2022 ; Reiken et al, 2022 ; Di Primio et al, 2023 ; Suzzi et al, 2023 ). A notable part of this feed-forward process is that microglial activation may be sustained via sterile DAMPs as IFN-I activators ( Roy et al, 2020 ) such as exosomal or insoluble tau ( Asai et al, 2015 ; Bolós et al, 2016 ) and errant nucleic acids ( Roy et al, 2020 ).…”

Section: Type I Interferon Signaling Dysregulation In the Brain Is A ...mentioning

confidence: 99%

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

Vavougios,

Tseriotis,

Liampas

et al. 2024

Front. Hum. Neurosci.

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COVID-19’s effects on the human brain reveal a multifactorial impact on cognition and the potential to inflict lasting neuronal damage. Type I interferon signaling, a pathway that represents our defense against pathogens, is primarily affected by COVID-19. Type I interferon signaling, however, is known to mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis and neuronal damage. In previous studies, we proposed a model of outside-in dysregulation of tonic IFN-I signaling in the brain following a COVID-19. This disruption would be mediated by the crosstalk between central and peripheral immunity, and could potentially establish feed-forward IFN-I dysregulation leading to neuroinflammation and potentially, neurodegeneration. We proposed that for the CNS, the second-order mediators would be intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without the requirement of neuroinvasion to sustain inflammation. Selective vulnerability of neurogenesis sites to IFN-I dysregulation would then lead to clinical manifestations such as anosmia and cognitive impairment. Since the inception of our model at the beginning of the pandemic, a growing body of studies has provided further evidence for the effects of SARS-CoV-2 infection on the human CNS and cognition. Several preclinical and clinical studies have displayed IFN-I dysregulation and tauopathy in gene expression and neuropathological data in new cases, correspondingly. Furthermore, neurodegeneration identified with a predilection for the extended olfactory network furthermore supports the neuroanatomical concept of our model, and its independence from fulminant neuroinvasion and encephalitis as a cause of CNS damage. In this perspective, we summarize the data on IFN-I as a plausible mechanism of cognitive impairment in this setting, and its potential contribution to Alzheimer’s disease and its interplay with COVID-19.

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Section: Tonic Type I Interferon Signaling Dysregulation As a Shared ...mentioning

confidence: 99%

Section: Tonic Type I Interferon Signaling Dysregulation As a Shared ...mentioning

confidence: 99%

Section: Type I Interferon Signaling Dysregulation In the Brain Is A ...mentioning

confidence: 99%

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

Vavougios,

Tseriotis,

Liampas

et al. 2024

Front. Hum. Neurosci.

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“…Dysfunctions of IFITMs and OASs on a pathway level not only have the potential to abrogate antiviral activity, but several studies suggest this dysfunction enables these factors to act as pro-viral factors ( 47 – 49 ). Vavougios and colleagues found that IFN-I signatures containing members of these ISG families are common in neurons, peripheral immune cells, and microglia affected by COVID-19 or by AD ( 10 , 15 , 33 , 50 , 51 ).…”

Section: The Viral Lifecycle: Kinase Recruitment and Tauopathymentioning

confidence: 99%

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

2022

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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.

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“…Detection of the virus even in the most detailed studies (Krasemann, Haferkamp, et al, 2022b;Matschke et al, 2020) is based on PCR amplification of short sections of genomic RNA and on some of the proteins of the virus, but not supported at the level of subgenomic mRNA evidence, which would indicate active viral transcription. The debates continue (Krasemann, Glatzel, & Pless, 2022a;Vavougios et al, 2022) and it has been proposed that in mice and in vitro models, not the whole virus but just the S protein (or its cleaved-off part, S1) is able to cross the BBB (Buzhdygan et al, 2020;Rhea et al, 2021). S1 may bind ACE2 in brain neurons and elevate levels of angiotensin II, inducing microglial activation and leading to tissue damage, within the paraventricular nucleus in the brain (Rodriguez-Perez et al, 2015).…”

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confidence: 99%

COVID‐19 and neurodegeneration: The mitochondrial connection

et al. 2022

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There is still a significant lack of knowledge regarding many aspects of the etiopathology and consequences of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in humans. For example, the variety of molecular mechanisms mediating this infection, and the long‐term consequences of the disease remain poorly understood. It first seemed like the SARS‐CoV‐2 infection primarily caused a serious respiratory syndrome. However, over the last years, an increasing number of studies also pointed towards the damaging effects of this infection has on the central nervous system (CNS). In fact, evidence suggests a possible disruption of the blood–brain barrier and deleterious effects on the CNS, especially in patients who already suffer from other pathologies, such as neurodegenerative disorders. The molecular mechanisms behind these effects on the CNS could involve the dysregulation of mitochondrial physiology, a well‐known early marker of neurodegeneration and a hallmark of aging. Moreover, mitochondria are involved in the activation of the inflammatory response, which has also been broadly described in the CNS in COVID‐19. Here, we critically review the current bibliography regarding the presence of neurodegenerative symptoms in COVID‐19 patients, with a special emphasis on the mitochondrial mechanisms of these disorders.

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SARS-CoV-2 and type I interferon signaling in brain endothelial cells: Blurring the lines between friend or foe

Cited by 4 publications

References 11 publications

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

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

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

COVID‐19 and neurodegeneration: The mitochondrial connection

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