SARS-CoV-2 may trigger inflammasome and pyroptosis in the central nervous system: a mechanistic view of neurotropism

Sepehrinezhad, Ali; Gorji, Ali; Negah, Sajad Sahab

doi:10.1007/s10787-021-00845-4

Cited by 24 publications

(17 citation statements)

References 97 publications

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“…In this study, we did observe histological lesions such as meningitis, perivascular inflammation, and gliosis in the brain and spinal cord of HEV-infected pigs with detectable viral RNAs in CNS tissues, thus suggesting that neuroinflammation might play a role in HEV-associated neurological injury. Therefore, future experiments are warranted to further investigate whether HEV, like other viruses such as HIV and severe acute respiratory syndrome coronavirus 2, induce neurological damages via induction of neuroinflammation ( 63 , 64 ).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

Tian

Heffron

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis E virus (HEV) is an important but understudied zoonotic virus causing both acute and chronic viral hepatitis. A proportion of HEV-infected individuals also developed neurological diseases such as Guillain–Barré syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in vitro blood–brain barrier (BBB) model, we first investigated whether HEV can cross the BBB and whether the quasi-enveloped HEV virions are more permissible to the BBB than the nonenveloped virions. We found that both quasi-enveloped and nonenveloped HEVs can similarly cross the BBB and that addition of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has no significant effect on the ability of HEV to cross the BBB in vitro. To explore the possible mechanism of HEV entry across the BBB, we tested the susceptibility of human brain microvascular endothelial cells lining the BBB to HEV infection and showed that brain microvascular endothelial cells support productive HEV infection. To further confirm the in vitro observation, we conducted an experimental HEV infection study in pigs and showed that both quasi-enveloped and nonenveloped HEVs invade the central nervous system (CNS) in pigs, as HEV RNA was detected in the brain and spinal cord of infected pigs. The HEV-infected pigs with detectable viral RNA in CNS tissues had histological lesions in brain and spinal cord and significantly higher levels of proinflammatory cytokines TNF-α and interleukin 18 than the HEV-infected pigs without detectable viral RNA in CNS tissues. The findings suggest a potential mechanism of HEV-associated neuroinvasion.

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Section: Discussionmentioning

confidence: 99%

Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

Tian

Heffron

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…5 Although many individuals develop asymptomatic or pauci-symptomatic infection, those ones with severe and critical disease exhibit a dysregulated over-activation of the immune system which can cause an abnormal immune response with impaired production of cytokines, which is likely to be responsible for most of the organ damage that occurs in the final stage of the disease. [10][11][12] To date, recent investigation has outlined that SARS-CoV-2 infection induces a pro-thrombotic state expressed mainly as immuno-thrombosis, that is, thrombotic events associated with inflammation in microcirculation, 5 an evidence even reported for SARS and in the very few post-mortem investigations (autoptic data), which we missed as a major evidence to shed a light on the real COVID-19 pathogenesis. [13][14][15][16] Autopsy, which was widely neglected to highlight and elucidate COVID-19 pathogenesis, is the most awkward 'missing link' to address COVID-19 pathogenesis, and hence a therapy protocol with the highest successful outcome.…”

Section: Introduction On the Immuno-thrombotic Etiopathogenesis Of Co...mentioning

confidence: 90%

“…Although many individuals develop asymptomatic or pauci‐symptomatic infection, those ones with severe and critical disease exhibit a dysregulated over‐activation of the immune system which can cause an abnormal immune response with impaired production of cytokines, which is likely to be responsible for most of the organ damage that occurs in the final stage of the disease 10–12 …”

Section: Introduction On the Immuno‐thrombotic Etiopathogenesis Of Co...mentioning

confidence: 99%

Home pharmacological therapy in early COVID‐19 to prevent hospitalization and reduce mortality: Time for a suitable proposal

Pandolfi

Chirumbolo

Ricevuti

et al. 2021

Basic Clin Pharma Tox

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The COVID-19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post-mortem autopsy was performed on a very modest number of patients who died from COVID-19 infection, leading to a first confirmation of an immune-thrombosis of the lungs as the major COVID-19 pathogenesis, likewise for SARS. Since then (June-August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti-inflammatory, anti-platelet, anticoagulant and antibiotic therapy confirmed that COVID-19 was an endothelial inflammation with immuno-thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immunethrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti-inflammatory therapy may treat endothelia inflammation and immune-thrombosis caused by COVID-19, by using drugs we are going to recommend in this paper.

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“…Additionally, IL-1β was shown to be upregulated and present in significantly higher levels in patients with COVID-19 requiring ICU admission [26]. It has been theorized that cytokine IL-1β plays a role in development of neurological complications of COVID-19 [27]. Although there are no current studies investigating the role of IL-1β in association with COVID-19 and development of epilepsy, given the evidence, it is possible IL-1β could play a role in epileptogenesis after COVID-19.…”

Section: Seizures and Epilepsy In Viral Infectionmentioning

confidence: 99%

SARS-CoV-2 infection and seizures: the perfect storm

Tsai¹,

Wilson²,

Rubiños³

2022

J. Integr. Neurosci.

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Seizures have been increasingly identified as a neurologic manifestation of coronavirus disease 2019 (COVID-19) infection. They may be symptomatic due to systemic infections, as a result of direct central nervous system (CNS) invasion, or occur in response to inflammatory reactions to the virus. It is possible that proinflammatory molecules released in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to hyperexcitability and epileptogenesis, similar to infections caused by other neurotrophic viruses. Cerebral spinal fluid (CSF) in patients with COVID-19 and seizures is negative for SARS-CoV-2 (PCR) in the majority of patients, but has been found to be positive for proinflammatory molecules like IL-6, IL-8, and anti-neuronal autoantibodies. Electroencephalogram (EEG) in COVID-19 patients are nonspecific. However, in the encephalopathic and critically ill subpopulation, EEG is essential in detecting nonconvulsive seizures and status epilepticus which is associated with increased overall mortality in COVID-19 patients. Thus, as encephalopathy is often the only CNS symptom evidenced in patients with nonconvulsive seizures, more judicious use of continuous EEG in encephalopathic COVID-19 patients should be considered. This would facilitate earlier detection and treatment of seizures in this population, which would ultimately improve outcomes. Further research into the onset and potential for development of seizures and epilepsy in patients with COVID-19 is needed.

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SARS-CoV-2 may trigger inflammasome and pyroptosis in the central nervous system: a mechanistic view of neurotropism

Cited by 24 publications

References 97 publications

Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

Home pharmacological therapy in early COVID‐19 to prevent hospitalization and reduce mortality: Time for a suitable proposal

SARS-CoV-2 infection and seizures: the perfect storm

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