Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity

Kyriakopoulos, Anthony M.; Nigh, Greg; McCullough, Peter A.; Seneff, Stephanie

doi:10.7759/cureus.32361

Cited by 17 publications

(21 citation statements)

References 147 publications

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“…In addition, the S1 subunit can induce neuroinflammation independently of SARS-CoV-2 infection [ 86 ]. This neuroinflammation can lead to an overexpression of PrPc, the normal form of the prion protein, and an activation of the amyloid precursor protein (APP) [ 87 ]. Moreover, the S2 subunit has been shown to interact with γ-secretase, an enzyme involved in the processes of amyloid beta-42 (Aβ42) formation from APP, increasing the production of this type of fibril [ 88 ].…”

Section: Reviewmentioning

confidence: 99%

Impacts of the SARS-CoV-2 Spike Protein on the Innate Immune System: A Review

Bocquet-Garçon

2024

Cureus

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The Spike protein enables the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to multiple receptors, including the angiotensin-converting enzyme 2 (ACE2). Scientific studies also indicate that Spike is involved in severe forms of coronavirus disease 2019 (COVID-19), "long-haul COVID diseases" - also known as "long COVID syndromes" or "post-acute sequelae of SARS-CoV-2 infection" (PACS) - or, recently, in adverse reactions to lipid nanoparticle-messenger ribonucleic acid (mRNA) vaccines or other anti-COVID19 products. Numerous mutations, notably within the subunit 1 of Spike (S1), prevent neutralization by antibodies, but more generally, the virus has developed numerous strategies to avoid immune system surveillance, especially type-I interferons (IFN-I). Meanwhile, a “hyperinflammatory” state, named “cytokine storm,” sets in. However, what role does the Spike protein play in the immune escape mechanisms? Can its inflammatory activities affect IFN-I? Does Spike block IFN-I or hijack them for the virus benefits? What are the other potential consequences? This article was written to provide an up-to-date and more general overview of the impact of the Spike protein on the innate immune system and its effectors at the molecular level.

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Section: Reviewmentioning

confidence: 99%

Impacts of the SARS-CoV-2 Spike Protein on the Innate Immune System: A Review

Bocquet-Garçon

2024

Cureus

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“…Most of the studies that reported syncytia-formation in virus-free systems that employed widely used model cell lines like HEK293T (human kidney cells), HeLa (human cancer cells), Calu-3 (human lung cells) or Huh-7 (human liver cells), which are overexpressing ACE2, and the used plasmid-based transfection systems further contribute to generate artificial conditions that limit a direct translation of the obtained results to realistic in vivo situations. On the other hand, the Spike protein encoded by the mRNA vaccines is stabilised in the prefusion-conformation to facilitate ACE2-binding and cell entry ( 303 ). It would be interesting to investigate to which degree syncytia formation is affected by this change versus ACE2 expression level ( 17 , 23 , 36 , 269 ).…”

Section: Spike and Dsdna Sensors In The Adverse Events After Covid-19...mentioning

confidence: 99%

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

Heil

2024

Front. Immunol.

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The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling and nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. The translation of the knowledge on how the resulting systemic inflammation can lead to life-threatening complications into novel treatments and vaccine technologies is underway. Nevertheless, previously existing knowledge on the role of cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported ‘de novo’ for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 to be outcomes of self-DNA-driven inflammation in fact had been linked earlier to self-DNA in different contexts, e.g., the infection with Human Immunodeficiency Virus (HIV)-1, sterile inflammation, and autoimmune diseases. I highlight particularly how synergies with other DAMPs can render immunogenic properties to normally non-immunogenic extracellular self-DNA, and I discuss the shared features of the gp41 unit of the HIV-1 envelope protein and the SARS-CoV 2 Spike protein that enable HIV-1 and SARS-CoV-2 to interact with cell or nuclear membranes, trigger syncytia formation, inflict damage to their host’s DNA, and trigger inflammation – likely for their own benefit. These similarities motivate speculations that similar mechanisms to those driven by gp41 can explain how inflammatory self-DNA contributes to some of most frequent adverse events after vaccination with the BNT162b2 mRNA (Pfizer/BioNTech) or the mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, autoimmune nephritis or hepatitis, new-onset systemic lupus erythematosus, and flare-ups of psoriasis or lupus. The hope is to motivate a wider application of the lessons learned from the experiences with COVID-19 and the new mRNA vaccines to combat future non-COVID-19 diseases.

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“…Antibodies to this sequence might bind the C-terminal of the prion protein due to molecular mimicry. Studies have shown that autoantibodies in the globular C-terminal domain can cause an aggressive form of CJD by interfering with the transport of the prion protein into the endoplasmic reticulum [ 40 ].…”

Section: Reviewmentioning

confidence: 99%

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review

Seneff¹,

Kyriakopoulos²,

Nigh³

et al. 2023

Cureus

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Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in many neurodegenerative diseases. Based on in vitro and in vivo experimental evidence relating to prion and prion-like disease, we extrapolate from the compelling evidence that the spike glycoprotein of SARS-CoV-2 contains extended amino acid sequences characteristic of a prion-like protein to infer its potential to cause neurodegenerative disease. We propose that vaccine-induced spike protein synthesis can facilitate the accumulation of toxic prion-like fibrils in neurons. We outline various pathways through which these proteins could be expected to distribute throughout the body. We review both cellular pathologies and the expression of disease that could become more frequent in those who have undergone mRNA vaccination. Specifically, we describe the spike protein’s contributions, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to further disease risk due to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and to other health complications. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We note with an optimism an apparent loss of prion-like properties among the current Omicron variants. We acknowledge that the chain of pathological events described throughout this paper is only hypothetical and not yet verified. We also acknowledge that the evidence we usher in, while grounded in the research literature, is currently largely circumstantial, not direct. Finally, we describe the implications of our findings for the general public, and we briefly discuss public health recommendations we feel need urgent consideration. An earlier version of this article was previously posted to the Authorea preprint server on August 16, 2022.

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Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity

Cited by 17 publications

References 147 publications

Impacts of the SARS-CoV-2 Spike Protein on the Innate Immune System: A Review

Impacts of the SARS-CoV-2 Spike Protein on the Innate Immune System: A Review

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review

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