Two studies explore the body's unique susceptivity to SARS-CoV-2 variants and vaccines

January 4, 2021 // --- People with different genetic variants in the immune system tend to have very different immune responses to SARS-CoV-2.
their reactions to vaccines will be different.
same reason, new mutations in SARS-CoV-2 can cause different immune responses in the same immune system.
in the larger reality we face today, all of these potential variations must be considered at the same time.
we recently discussed several sources of newly discovered immune gene variants that control SUS-CoV-2 susceptibleness.
, for example, modern people carrying the Neanderthal gene DEP4 or the protease TMPRSS2 of the protease TPRSS2 appear to have a higher risk of severe COVID-19.
other variants, such as those commonly found in East Asians that express the TMEM1B gene or the heparin sulfate synthesis pathway, help explain the disproportionate severity of COVID-19 in some populations.
two papers--- one was recently published in the journal Nature Immunology and the other was recently published in the journal Science--- extending the list of emerging genes to include antibody structural variations caused by viruses or vaccines.
these variants include a special post-translational modification of the rich IgG1 subsype anti-RBD (subject binding domain) antibody, called deyan algae glycosylation.
this essentially means that, for one reason or another, antibodies that deyan algae glycosylate are missing a algal sugar molecule at key structural locations.
images from Science, 2020, doi:10.1126/science.abc8378.
to better understand the effects of the lack of algal sugar molecules, consider the standard IgG antibody molecular structure.
the variable part of the IgG antibody, the arms of the Y-shaped antibody molecule, is called the Fab region and contains a vertephrase that interacts with the viral prick protein.
area of the IgG antibody contains a constant Fc fragment, and by the way, the glyco-based modifier located at the N297 bit may contain algal sugar.
in a specific feature that is almost like a deformation, this glycosylated modifier also has a bi-tentacle structure similar to the mother antibody, which is much smaller and uses a variety of sugars instead of amino acids.
algal sugar itself hangs from the stem of the sugar aggregate, just as the sugar aggregate hangs on the antibody.
for those familiar with a related post-translation modification type called ubibinization, N-polysaccharide connections form a code, much like the so-called ubiganized code.
Ubiquitin code consists of linear sub-base and branch sub-base of various phosphate or acetylation ubiquitin (SUMO or NEDD), while N-polysaccharide code consists of a heptose core that can be further expanded with core algal sugar, end semi-lactose (Gal), end salivary acid (Sia) and second-class GlcNAc through selective enzyme-based glycosylation reactions.
authors of the two new papers found that patients with severe COVID-19, especially men, were more likely to develop IgG1 antibodies with deyan algae-based Fc polysaccharine.
that the net result of deyan algae glycosylation is enhanced interaction and binding with the immunely activated Fc-Fc-RiIA.
this then increases the production of cytokines such as IL-6 and TNF in monocytes.
note that typical Fc subjects of human IgG include activated Fc-RI, Fc-RIIA, Fc-RIIC, Fc-RIIA, and Fc-RIIB, and inhibitory Fc-RIIB.
most immune-effect cells simultaneously express active and inhibitory Fc-R, the net result of IgG interactions can usually be predicted as the ratio of binding affinity between specific active IgG receptors and inhibitory IgG receptors.
the researchers first isolated the associated IgG from the patient's serum using protein purification and trypsin digestion.
nanoscale liquid chromatography-series mass spectrometrography techniques are commonly used to indicate potential glycosylation points.
, what they really want is a more quantitative description of the extent to which the binding of the subject is affected by deyan algae glycosylation.
to this end, a wide range of proven biophysical technologies are available, including surface plasma resonance (SPR), isothermal drop rationing (ITC), microscale heat (MST), and biosurface interferometry (BLI).
the authors of the Nature Immunology paper chose to use bio-layer interferometry (BLI), which produces a binding graph (in nanometers) as a time function from which they can derive dynamic constants.
BLI is an optical, labelless technique that analyzes the interference patterns of white light reflected from two surfaces.
surface is a fixed protein layer located on the tip of a biosensors, while the other surface is an internal reference.
the changing interference patterns can be measured in real time when the dosing fixed to the tip surface of the biosensor binds to the analyte in the solution.
deyan algae glycosylated IgG was found to have a 20-40-fold increase in affinity with Fc-RIIIa.
this helps explain the observed activation of the front-line lung scavengers, or pulmonary macrophages, that express Fc-RIIA into antibody-dependent cells.
Although a decrease in Fc algal glycosylation can be seen in the anti-prickly protein response in patients with acute respiratory distress syndrome (ARDS), other studies have found high levels of algal glycosylation in several cancers.
when trying to produce high-titration recovery immunoglobulin drugs, it may be important to use plasma rich in algal glycosylated anti-SARS-CoV-2 antibodies.
algae glycosylated IgGs that form targeted viruses generally mediate stronger Fc-RIIia responses, they tend to amplify cytokine storms and immunopathology.
While mutations in many genes that help build polysaccharid chains, such as the coding gene for the viscose-based metastase FUT2, may be expected to play a role in patient responses, perhaps a more pressing concern is differences in antibody responses to vaccines.
series of good news, the actual nucleic acid sequence of Pfizer's new mRNA vaccine was generously made public.
to respond and try to decipher the revelation was a man named Bert Hubert, who quickly interpreted the news for us.
the main difference in the code for this mRNA vaccine is that urine is replaced by 1-methyl-3'-fake urine glycoside (labeled Ψ).
although Ψ does not induce activation of our immune system, it is still accepted as normal uracils by cell translation, transcription, and replication complexes.
other strange features are the replacement of two prolines to stabilize the SARS-CoV-2 protrusion structure, as well as the deployment of special 5' and 3' non-translated areas before and after the main tingling protein coding sequence.
Bert has promised to release a second in-depth study of the series in a few days, which is certainly something many are eagerly awaiting.
(Bioon.com) Reference: 1. Saborni Chakraborty et al. Proinflammatory IgG Fc structures in patients with severe COVID-19. Nature Immunology, 2020, doi:10.1038/s41590-020-00828-7.2.Mads Delbo Larsen et al. Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science, 2020, doi:10.1126/science.abc8378.3.Unique susceptibility to unique Sars-CoV-2 variants and vaccines