SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy

Datta, Gaurav; Miller, Nicole; Halcrow, Peter W.; Khan, Nabab; Colwell, Timothy; Geiger, Jonathan D.; Chen, Xuesong

doi:10.3389/fncel.2021.777738

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…In testing the hypothesis that the S1 protein of SARS-CoV-2 can directly induce neuronal injury, Datta et al (Datta et al, 2021) demonstrated that the exogenous S1 protein leads to endolysosomal dysfunction and dystrophy of neurons. These processes can also disrupt the transport of synaptic vesicle precursors, lysosomes and autophagic components (Datta et al, 2021). The authors correctly suggested that S1 is involved in the high incidence of neurological and psychological manifestations of SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

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Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines

2022

I J Infectious Disea

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This review/analysis gives a first impression of numerous adverse events related to Covid-19 vaccination, which have received little attention to date, are often unexplained, but are nevertheless very distressing. Frequently observed organ-related ADRs after Covid-19 vaccination were such of the nervous system, musculoskeletal system, gastrointestinal tract, and skin. The involvement of almost all organs in the side effect spectrum of Covid-19 vaccines demonstrates their systemic efficacy. As shown by the ADRs occurrence even after numerous days to weeks, the duration of spike production obviously lasts longer than claimed. The key role is played by the interaction between the spike subunit S1 and the membrane-bound enzyme ACE2, the receptor for SARS-CoV. Downregulation of ACE2 by spikes and following activation of RAAS can lead to numerous clinically relevant disorders, such as vasoconstriction, tissue ischemia, induction of proliferative processes, increased oxidative stress, inflammation, or coagulation disorders, as previously shown for cardiovascular reactions. It is proposed to use the collective term “SPAS” (in German: Spike ausgelöste Störungen) - spike induced disturbances for side effects based on this mode of action. The common mode of action and only slightly different frequencies of adverse events and fatal outcomes do not indicate any principal differences in adverse event profiles of the individual spike-based Covid-19 vaccines. A class-specific side effect profile can be assumed. Knowledge and awareness of the comprehensive adverse event profile of the novel Covid-19 vaccines and their potential dangerousness may improve vaccine safety.

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Section: Discussionmentioning

confidence: 99%

“…Erickson et al, 2021);(Datta et al, 2021). Also, cross-reactions of antibodies or T-cells that misidentify inner ear antigens as viruses are capable of causing damage as well (DiMauro et al, 2022).…”

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confidence: 99%

Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines

2022

I J Infectious Disea

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“…3 B, C), indicating heightened synaptic transmission and neuronal excitability. Despite the fact that whether SARS-CoV-2 spike protein increases or decreases neuronal activity is controversial (37)(38)(39)(40). this observation is noteworthy, as it suggests that the spike protein, when directly interacting with neurons, has the potential to amplify their responsiveness to incoming signals.…”

Section: Spike Protein Increases Microglia-dependent Field Epsps (Fep...mentioning

confidence: 99%

SARS-CoV-2 neurotropism-induced anxiety/depression-like behaviors require Microglia activation

Ge,

Zhou,

Porras

et al. 2023

Preprint

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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with a wide range of “long COVID” neurological symptoms. However, the mechanisms governing SARS-CoV-2 neurotropism and its effects on long-term behavioral changes remain poorly understood. Using a highly virulent mouse-adapted SARS-CoV-2 strain, denoted as SARS2-N501YMA30, we demonstrated that intranasal inoculation of SARS2-N501YMA30results in viral dissemination to multiple brain regions, including the amygdala and hippocampus. Behavioral assays show a significant increase in anxiety- and depression-like behaviors 14 days following viral infection. Moreover, we observed microglia activation following SARS2-N501YMA30infection, along with an augmentation in microglia-dependent neuronal activity in the amygdala. Pharmacological inhibition of microglial activity subsequent to viral spike inoculation mitigates microglia-dependent neuronal hyperactivity. Furthermore, transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating microglia-driven neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Overall, these data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.

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“…As described above, it is a matter of debate whether SARS-COV-2 can enter the brain, but several studies indicate that the SARS-CoV-2 S1 protein can be released from viral membranes, can cross the BBB, and is present in brain cells including neurons ( Meinhardt et al, 2021 ; Rhea et al, 2021 ; Petrovszki et al, 2022 ). Thus, Datta et al (2021) tested the hypothesis that SARS-CoV-2 S1 protein can directly induce neuronal injury. The latter authors found that the S1 protein accumulates in endolysosomes of human cortical neurons and induces aberrant endolysosome morphology and neuritic varicosities, which could contribute to the high incidence of neurological disorders associated with COVID-19.…”

Section: Mechanisms Of Seizures and Epilepsy Associated With Viral In...mentioning

confidence: 99%

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

Löscher

Howe

2022

Front. Mol. Neurosci.

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Seizures are a common presenting symptom during viral infections of the central nervous system (CNS) and can occur during the initial phase of infection (“early” or acute symptomatic seizures), after recovery (“late” or spontaneous seizures, indicating the development of acquired epilepsy), or both. The development of acute and delayed seizures may have shared as well as unique pathogenic mechanisms and prognostic implications. Based on an extensive review of the literature, we present an overview of viruses that are associated with early and late seizures in humans. We then describe potential pathophysiologic mechanisms underlying ictogenesis and epileptogenesis, including routes of neuroinvasion, viral control and clearance, systemic inflammation, alterations of the blood-brain barrier, neuroinflammation, and inflammation-induced molecular reorganization of synapses and neural circuits. We provide clinical and animal model findings to highlight commonalities and differences in these processes across various neurotropic or neuropathogenic viruses, including herpesviruses, SARS-CoV-2, flaviviruses, and picornaviruses. In addition, we extensively review the literature regarding Theiler’s murine encephalomyelitis virus (TMEV). This picornavirus, although not pathogenic for humans, is possibly the best-characterized model for understanding the molecular mechanisms that drive seizures, epilepsy, and hippocampal damage during viral infection. An enhanced understanding of these mechanisms derived from the TMEV model may lead to novel therapeutic interventions that interfere with ictogenesis and epileptogenesis, even within non-infectious contexts.

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SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy

Cited by 10 publications

References 47 publications

Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines

Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines

SARS-CoV-2 neurotropism-induced anxiety/depression-like behaviors require Microglia activation

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

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