Immunology

Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis.

 

These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.

 

Published (Julay 14, 2023) in Sig Transduct Target Ther. :

https://doi.org/10.1038/s41392-023-01556-8 

Via Juan Lama

Epstein-Barr virus (EBV) reactivation resulting from the inflammatory response to coronavirus infection may be the cause of previously unexplained long COVID symptoms—such as fatigue, brain fog, and rashes—that occur in approximately 30% of patients after recovery from initial COVID-19 infection. The first evidence linking EBV reactivation to long COVID, as well as an analysis of long COVID prevalence, is outlined in a new long COVID study published in the journal Pathogens.  "We ran EBV antibody tests on recovered COVID-19 patients, comparing EBV reactivation rates of those with long COVID symptoms to those without long COVID symptoms," said lead study author Jeffrey E. Gold of World Organization. "The majority of those with long COVID symptoms were positive for EBV reactivation, yet only 10% of controls indicated reactivation." The researchers began by surveying 185 randomly selected patients recovered from COVID-19 and found that 30.3% had long term symptoms consistent with long COVID after initial recovery from SARS-CoV-2 infection. This included several patients with initially asymptomatic COVID-19 cases who later went on to develop long COVID symptoms.

 

The researchers then found, in a subset of 68 COVID-19 patients randomly selected from those surveyed, that 66.7% of long COVID subjects versus 10% of controls were positive for EBV reactivation based on positive EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM titers. The difference was significant (p < 0.001, Fisher's exact test). "We found similar rates of EBV reactivation in those who had long COVID symptoms for months, as in those with long COVID symptoms that began just weeks after testing positive for COVID-19," said coauthor David J. Hurley, Ph.D., a professor and molecular microbiologist at the University of Georgia. "This indicated to us that EBV reactivation likely occurs simultaneously or soon after COVID-19 infection." The relationship between SARS-CoV-2 and EBV reactivation described in this study opens up new possibilities for long COVID diagnosis and treatment. The researchers indicated that it may be prudent to test patients newly positive for COVID-19 for evidence of EBV reactivation indicated by positive EBV EA-D IgG, EBV VCA IgM, or serum EBV DNA tests. If patients show signs of EBV reactivation, they can be treated early to reduce the intensity and duration of EBV replication, which may help inhibit the development of long COVID. "As evidence mounts supporting a role for EBV reactivation in the clinical manifestation of acute COVID-19, this study further implicates EBV in the development of long COVID," said Lawrence S. Young, Ph.D., a virologist at the University of Warwick, and Editor-in-Chief of Pathogens. "If a direct role for EBV reactivation in long COVID is supported by further studies, this would provide opportunities to improve the rational diagnosis of this condition and to consider the therapeutic value of anti-herpesvirus agents such as ganciclovir."

 

Original findings published in Pathogens (June 10, 2021):

https://doi.org/10.3390/pathogens10060763

Via Juan Lama