Endotoxins Embedded in FCS of SARS-CoV-2
The role of LPS and S proteins in Covid-19 symptomps and outcomes.
The debates about Covid-19 and the virus, SARS-CoV-2 haven't over yet. Recent data about the ADE in Covid-19 vaccines are adding the oils to the debates. Nevertheless, the fatal cases are not just numbers, they are human beings who had lost their lives. Think about them what if they are one of our family, loved ones, friends.
In February 2020 when the whole world knew about Covid-19 as a pandemic, people were told to watch for the symptomps of respiratory system. Then the confusion rose as the positive numbers tested for SARS-CoV-2 were also had showed symptomps in gastrointestinal, renal, cardiac, neuroinvasion, and skin. Some blamed the co-infections and the second infections in Covid patients.
Though there are such cases, the molecular structure and genomics sequencing of SARS-CoV-2 drive the attention to the cleavage of S1/S2 proteins. Lipopolysaccharides (LPS) within the cleavage were found. The most frequently sampled binding site of S protein-LPS (21 out of 40 poses) were found within the proximity of the S1/S2 furin cleavage site (FCS).
LPS, also known as endotoxins, induces a strong response from normal animal immune systems. LPS is the major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS is the most abundant antigen on the cell surface of most Gram-negative bacteria, contributing up to 80% of the outer membrane of E. coli and Salmonella.
Impaired intestinal absorption is a major mechanism for diarrhea caused by endotoxin lipopolysaccharide (LPS) and is generally accompanied with damage to the intestine. During severe bacterial infection, endotoxin LPS would be released due to the breakdown of the cell wall of Gram-negative bacteria.
Cardiorenal syndrome (CRS) type 5, secondary to the septic state, is characterized by a combination of direct and indirect effects of endotoxin which induces the release of a huge array of pro- and anti-inflammatory mediators, implicated in the pathogenesis of cardiac and renal dysfunctions.
A bacterial endotoxin-based experimental model of
Parkinson's disease reported neurodegeneration. It provided mechanisms of neuroinflammation-mediated dopaminergic neuron loss.
In SARS-CoV-2 S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) activation. LPS is recognized by the toll-like receptors (TLRs) on the cell surface of macrophages. TLR4 recognizes bacterial LPS. It is a powerful pathway best known for inducing inflammation in response to bacteria-produced LPS. Under normal conditions, TLR4 is expressed mainly in macrophages and, at a lower level, in epithelial, endothelial, and stromal cells. Activated TLR4 significantly increases inflammatory cytokines.
LPS can lead to vascular endothelial barrier dysfunction, which often results in acute lung injury and acute respiratory distress syndrome (ARDS), a symptomps frequently found in Covid patients. LPS, the main component of the cell walls of Gram-negative bacteria, destroys the barrier function of human pulmonary microvascular endothelial cells (HPMECs) and plays an important role in the development of sepsis. Disruption of the pulmonary endothelial barrier is a hallmark of sepsis and ALI (acute lung injury) and ARDS. Sepsis is a life-threatening complication of an infection. Patients with a systemic inflammatory response such as in sepsis show increased levels of LPS in plasma, with levels ranging from 0.1 to 1 ng/ml. LPS at doses of 0.5–1 ng/ml, combined with SARS-CoV-2 S protein, yielded response levels as produced by 10 ng/ml LPS. LPS with 50 pg/ml showed high number of tumor necrosis factor alpha (TNF-α) and IL-6 levels together with S protein.
LPS reduced the vascular permeability and endothelial cell proliferation. Vasculature undergoes structural change to decrease vascular permeability in response to systemic LPS administration. This condition will bring the patients to microvascular leakages and blood clots.
S protein of SARS-CoV-2 modulated the aggregation state of LPS. There is a link between excessive inflammation during infection of SARS-CoV-2 and increased levels of bacterial endotoxins. LPS could bind to the related SARS-CoV S protein. The affinity of LPS to SARS-CoV-2 S protein was in the range of the one observed for LPS binding to the human receptor CD14 (antibody part of human innate immunity system).
In Covid vaccines, the pre-fusion-stabilized version of SARS-CoV-2 S-protein contains two proline substitutions (2P). Structural studies reveal that the pre-fusion stabilized S closely resembles native S protein on the virion surface; a structure targeted by many reported effective neutralizing antibodies. Since these vaccines resembles native S protein on the virion surface, a thorough research is needed whether the endotoxins effects are there in the vaccines. It may be the answers of many ADEs of the vaccinated.
Sources:
https://www.ahajournals.org/doi/full/10.1161/01.atv.0000081741.38087.f9
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205337/#:~:text=It%20has%20been%20reported%20that,lumen%20to%20the%20blood%20stream.
https://www.karger.com/Article/Fulltext/480424
https://www.hindawi.com/journals/pd/2011/487450/
https://academic.oup.com/jmcb/article/12/12/916/6028992
https://en.m.wikipedia.org/wiki/Lipopolysaccharide#:~:text=Lipopolysaccharides%20(LPS)%2C%20also%20known,membrane%20of%20Gram%2Dnegative%20bacteria
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028427/
https://pubmed.ncbi.nlm.nih.gov/27609286/
https://www.biorxiv.org/content/10.1101/2020.10.14.337535v1.full.pdf
Pictures taken from:
https://academic.oup.com/jmcb/article/12/12/916/6028992