Tag: covid spike protein

Inhibition of HIF-2α Pathway as a Potential Therapeutic Strategy for Endothelial Dysfunction in Post-COVID Syndrome

Abstract:

Background SARS-CoV-2 infection may lead to Post-COVID Syndrome (PCS), characterized by debilitating symptoms like persistent fatigue, cardiovascular symptoms, and cognitive dysfunction. Persistent endothelial dysfunction (ED) is a potential driver of ongoing symptoms. Yet, the underlying biological mechanisms remain unclear.

Methods In this prospective observational study, we characterized 41 PCS patients and 24 healthy controls (HC, matched out of n = 204, recruited before the pandemic) and investigated the effect of SARS-CoV-2 Spike protein 1 (S1) and plasma from PCS patients on human retinal endothelial cells (HREC).

Results Plasma samples from PCS patients exhibited significantly elevated erythropoietin, VEGF and MCP-1 alongside decreased IL-6 levels compared to HC. Low Haemoglobin and Haematocrit were negatively associated with PCS severity. VEGF levels were positively correlated with Anti-S1 IgG levels in patients and upregulated on mRNA level in HREC exposed to S1. Additionally, S1 exposure promoted ROS production and transiently activated HIF-1α in HREC. Persistent activation of HIF-2α by S1 led to disrupted endothelial integrity. HREC exposed to plasma from severely affected PCS patients showed increased ROS and compromised barrier function. Treatment with Belzutifan, a HIF-2α inhibitor, restored barrier integrity in HREC exposed to S1 or PCS-plasma.

Conclusion These findings suggest that HIF-2α-mediated ED in PCS might be a potential therapeutical target for Belzutifan.

Trial registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05635552

What Is Known?

  • Endothelial dysfunction (ED) is a consequence of acute SARS-CoV-2 infection and may lead to Post-COVID syndrome (PCS) symptoms.

  • Patients with PCS show elevated inflammation and endothelial dysfunction markers.

  • Spike proteins can persist for up to 12 months post-infection, driving ongoing inflammation and immune activation.

What New Information Does This Article Contribute?

  • Low haemoglobin (Hb) and high VEGF correlate with higher Anti-S1 IgG and low Hb is associated with higher C19-YRS severity score.

  • PCS patients exhibit higher Erythropoietin (EPO) levels when compared to HC.

  • Spike protein 1 (S1) alone and PCS patient’s plasma induce endothelial dysfunction primarily through HIF-2α activation.

  • Both S1 and PCS plasma cause oxidative stress and disrupting endothelial integrity.

  • Inhibition of HIF-2α effectively restores endothelial barrier integrity disrupted by S1 and PCS plasma.

What New Information Does This Article Contribute? Persistent circulation of spike proteins can sustain chronic inflammation and immune activation in patients with PCS. Here we show that plasma from PCS patients exhibits significantly elevated levels of VEGF which positively correlates with Anti-S1 IgG. Low haemoglobin was associated with higher Anti-S1 IgG titres and correlated with a higher C19-YRS severity score. Levels of EPO were higher in PCS patients, with a more pronounced effect observed in patients with cardiovascular symptoms. In human retinal endothelial cells, both S1 and plasma from PCS patients primarily induce ED through HIF-2α activation, rather than NF-κB. Both factors lead to significant oxidative stress, evidenced by increased ROS production which in turn disrupts endothelial barrier integrity and function. Notably, Belzutifan, a HIF-2α inhibitor, can restore this compromised endothelial function, offering a potential therapeutic target for PCS.

Source: Andrea Ribeiro, Timon Kuchler, Maciej Lech, Javier Carbajo-Lozoya, Kristina Adorjan, Hans Christian Stubbe, Martina Seifert, Anna Wöhnle, Veronika Kesseler, Johanna Negele, Uwe Heemann, Christoph Schmaderer. Inhibition of HIF-2α Pathway as a Potential Therapeutic Strategy for Endothelial Dysfunction in Post-COVID Syndrome medRxiv 2024.09.10.24313403; doi: https://doi.org/10.1101/2024.09.10.24313403 https://www.medrxiv.org/content/10.1101/2024.09.10.24313403v1.full-text (Full text)

The Long Covid-19 Syndrome the Spike Protein and Stem Cells, the Underrated Role of Retrotransposons, a Working Hypothesis

Abstract

Coronavirus disease-2019 (COVID-19) was seen as a respiratory disease, however, an increasing number of reports indicated that the spike protein could also be the cause of the long-term post-infectious conditions known as Long-COVID characterized by a group of unresponsive idiopathic severe neuro, cardio-vascular disorders, including strokes, cardiopathies, neuralgias, fibromyalgia, and Parkinson’s like-disease. Different lines of pieces of evidence confirmed that the spike protein that can be found on the surface of the SARS-CoV-2 virus latches onto angiotensin-converting enzyme 2 (ACE2) receptors located on target cells.
The RNA genome of coronaviruses, which, has a median length of 29 kb and is the longest among all RNA viruses, is comprised of six to ten open reading frames (ORFs) that are responsible for encoding both the replicase and structural proteins for the virus. Each of the components of the viral genome is packaged into a helical nucleocapsid that is surrounded by a lipid bilayer. The viral envelope of coronaviruses is typically made up of three proteins that include the membrane protein (M), the envelope protein (E), and the spike protein (S). The spike protein not only facilitates the virus entry into healthy cells, which is the first step in infection but also promote profound damage to different organs and tissues leading to severe impairments and long-term disabilities.
Here, we discussed the pervasive mechanism that spikes mRNA adopted to alter multipotent and pluripotent stem cell (SCs) genomes and the acquired disability of generating an infinite number of affected clonal cells. This stance is based on the molecular and evolutionary aspects obtained from retrotransposons-retrotransposition in mammalians and humans that documented the frequent integration of mRNA molecules into genomes and thus into DNA. Retrotransposition is the molecular process in which transcribed and spliced mRNAs are accidentally reverse-transcribed and inserted into new genomic positions to form a retrogene.
Sequence-specific traits of mRNA clearly showed long interspersed element-1 (LINE-1 or L1) to confirm the retrotransposition, considered the most abundant autonomously active retrotransposons in the human genome. In mammals, L1 retrotransposons drive retrotransposition and are composed of long terminal repeats (LTRs) and non-LTR retrotransposons (mainly long interspersed nuclear elements or LINEs); specifically, the LTR-mediated retrocopies are immediately cotranscribed with their flanking LTR retrotransposons.
In response to retrotransposons transposition, stem cells (SCs) employ a number of silencing mechanisms, such as DNA methylation and histone modification. This manuscript theorizes the expression patterns, functions, and regulation of mRNA Spike protein imprinted by SCs retrotransposons which generate unlimited lines of affected cell progenies and tissues as the main condition of untreatable Spike-related inflammatory conditions.
Source: Balzanelli, M.G.; Distratis, P.; Lazzaro, R.; Dipalma, G.; Inchingolo, F.; Del Prete, R.; Hung Pham, V.; Aityan, S.K.; Nguyen, K.C.; Isacco Gargiulo, C. The Long Covid-19 Syndrome the Spike Protein and Stem Cells, the Underrated Role of Retrotransposons, a Working Hypothesis. Preprints 2023, 2023081130. https://doi.org/10.20944/preprints202308.1130.v1 https://www.preprints.org/manuscript/202308.1130/v1 (Full text available as PDF file)

SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

Abstract:

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus’s acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis.

Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike’s persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway.

Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.

Source: Zhouyi Rong, Hongcheng Mai, Saketh Kapoor, Victor G. Puelles, Jan Czogalla, Julia Schädler, Jessica Vering, Claire Delbridge, Hanno Steinke, Hannah Frenzel, Katja Schmidt, Özüm Sehnaz Caliskan, Jochen Martin Wettengel, Fatma Cherif, Mayar Ali, Zeynep Ilgin Kolabas, Selin Ulukaya, Izabela Horvath, Shan Zhao, Natalie Krahmer, Sabina Tahirovic, Ali Önder Yildirim, Tobias B. Huber, Benjamin Ondruschka, Ingo Bechmann, Gregor Ebert, Ulrike Protzer, Harsharan Singh Bhatia, Farida Hellal, Ali Ertürk. SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19. bioRxiv 2023.04.04.535604; doi: https://doi.org/10.1101/2023.04.04.535604 https://www.biorxiv.org/content/10.1101/2023.04.04.535604v1.full (Full text)