Archive 20/12/16

Relationship between N-glycans of HIV envelope protein and infectivity and neutralizing antibodies

HIV is a virus with envelope proteins in the same way as SARS-CoV-2, and there have been numerous studies on the structure and glycan modification of that protein. The envelope protein of HIV is called gp160 and is made up of two sub-units, gp41 and gp120. HIV infection is initiated by gp120 binding to CD4 receptors on T cells. Gp120 has 27 N-type glycan modification sites and is known to be strongly glycosylated with high mannose.

A group of Univ. of Alabama at Birmingham has reported about the effects of gp120 glycosylation on infectivity and neutralizing antibodies.
https://pubmed.ncbi.nlm.nih.gov/33205023/

As a result, it was confirmed that the infectivity increased by 7 to 9 times when there was N262 glycan modification.
In addition, it was found that N262 glycan modification reduces the neutralization capacity of HIV neutralizing antibodies.
In particular, PGT151, 35022, 2G12, VRC24, PG16, and PGT145 showed a significant decrease in the capacity.

In this paper, they have discussed possible mechanisms behind these changes using molecular dynamics models.

The new coronavirus (SARS-CoV-2) is an artificial product no matter how you think about it

There is a noteworthy paper on the origin of the novel coronavirus (SARS-CoV-2).
https://zenodo.org/record/4073131?fbclid=IwAR2VprdWCGzl8NlNpzWPz0QudcBRHZ0dnPPCZNz8Yg2oGfleP1_ZxoipzEI

The central points of the discussion are:

RaTG13 (96.2%) hosted by horseshoe bat and MP789 (90.1%) hosted by pangolin are close to SARS-CoV-2.
But,

  1. Syn/non-syn ratio of spontaneous gene mutations must not fluctuate significantly across the entire region of the S protein, whereas SARS-CoV-2 vs RaTG13 fluctuates over an order of magnitude.
  2. The amino acid sequences in the receptor binding domain (RBD) of S proteins should best bind to the host’s infected receptors, but RaTG13 and pangolin coronavirus do not bind much to ACE2 of their hosts, horseshoe bat or pangolin.
  3. The E protein of ZC45, ZXC21, which is coronavirus in bats, is the same as 100% SARS-CoV-2 and could be the backbone of the SARS-CoV-2 gene sequence.
  4. How the furin-cleavage site inserted at the junction of the S1/S2 region could not be rationally explained from a view point of viral evolution.

When I start reading this paper, I’m drawn in as if I were reading a detective story.
And finally, you will be convinced that the new coronavirus (SARS-CoV-2) could be an artificial product.

By all means, I recommend you to read it.

The fact that the elderly are more likely to develop severe disease in the new coronavirus (COVID-19) is caused by the presence or absence of cross-reticulation with conventional human coronavirus (HCoVs)

It is well known that covid-19 is prone to develop severe diseases in the elderly and underlying diseases (such as diabetes, cerebrovascular diseases and hypertension etc.).
There are various discussions about the difference between the elderly and the young, such as that young people have stronger innate immunity, and in the elderly, the balance between innate and acquired immunity is broken.

The following group believes that why COVID-19 becomes severe in the elderly would be related to the presence or absence of T-cell cross-reactions specific to conventional human coronaviruses (strains such as HCoVs: NL63, OC43).
https://www.nature.com/articles/s41598-020-78506-9

From this study, it was confirmed that T-cell immunity induced by human α-HCoV (NL63) and β-HCoV (OC43) was present in young adults, but virtually not in the elderly, and the frequency of cross-reactive T-cells directed to novel coronavirus (SARS-CoV-2) was minimal in most elderly. Indeed, it is likely to be related to the severity of the elderly.

 

 

 

Difference in IFN-γ response,
<10 (black), 10–30= (dark gray), 30–100 (green), 100–200 (light gray), >200 (Orange) SFU/10^6 PBMC.

A new therapy for the new coronavirus (COVID-19): Topoisomerase 1 inhibitors suppress gene transcription induced by SARS-CoV-2 infection “in one go”

It is well known that when the new coronavirus (COVID-19) becomes severe, it causes acute respiratory prompt syndrome and multiple organ failure, resulting in cytokine storms.
To mitigate lung inflammation, the use of inhibitors against certain cytokines, such as IL-6 and GM-CSF, is limited. This is because there are many signaling molecules and pathways are involved in the triggering of cytokine storms.
Therefore, the following group focused on inhibitors of DNA Topoisomerase-1 in order to inhibit the transcription process of genes induced by viral infection “in one go”
https://pubmed.ncbi.nlm.nih.gov/33299999/

Topoisomerase-1 is a necessary enzyme to unwind DNA double helix.
In vivo experiments using hamsters, it was shown that genes expressed high by viral infection were down regulated by the Topoisomerase-1 inhibitor, and thereby SARS-CoV-2-induced lung
inflammation was suppressed.

Conditions of the new coronavirus (COVID-19) can be mimicked by a SARS-CoV-2 protein cocktail (S, N, P-protein)

A group of La Paz University Essential, Spain has suggested a treatment based on the novel coronavirus (COVID-19) symptoms that can be completely mimicked by a protein cocktail of SARS-CoV-2.
https://pubmed.ncbi.nlm.nih.gov/33283062/

In patients with COVID-19, inflammation and cytokine storms are induced, and il-1β, IL-6, and TNF-α are known to be highly expressed. This early stage can be explained by excessive activation of monocytes and macrophages. In the later stages of COVID-19, adaptive immunity plays a critical role, and in severe patients, lymphocytes are significantly reduced.

Blood cells obtained from healthy people was incubated with SARS-CoV-2 S-protein, N-protein and P-protein cocktails and developed a phenotype that mimics the COVID-19 condition. For example, in monocytes, HLA-DR, the signal path for antigen presentation, was reduced, and PD-L1, a immune checkpoint ligand, was highly expressed.
From these results, it was suggested that the use of inhibitors (antibodies) for immune checkpoint molecules could lead to effective treatment. Actually, a clinical trial using camrelizumab (PD-1 antibody) is in progress.

Expect progress.

Importance of β3Gn-T6 Glycosyltransferase (enzyme involved in the synthesis of Core3 O-glycan) in pancreatic ductal adenocarcinoma

It is well known that changes in the expression of mucin-type O-glycans can be seen in the initiation, progression, and metastasis of cancers.
A group of AIST has reported a study on the relationship between clinicopathology and O-glycans in pancreatic ductal adenocarcinoma.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242851

In pancreatic ductal adenocarcinoma, Tn-antigen and sialyl-LewisX antigen are highly expressed.
However, there was no correlation between these expression levels and disease-free survival (DFS).
Interestingly, however, there was a clear correlation between β3Gn-6T glycosyltransferase and DFS, indicating that higher expression of β3Gn-6T resulted in longer DFS.
The β3Gn-6T glycosyltransferase is a necessary enzyme for the synthesis of Core3 O-glycans.

At this stage, the mechanism of why the Core3 structure and its extended structure increase DFS is not known.
Let’s look forward to the progress of research in the future.  That may lead to the outcome of breaking down the general concern that “Glycan is just a physiological expression of disease state”, .

Simplified sample preprocessing of RT-PCR in novel coronavirus (SARS-CoV-2) detection: heat treatment only

RT-PCR is the Gold Standard for testing for covid-19. Samples are taken from the nasal cavity with cotton swabs, nucleic acids are extracted by pre-treatment, and then RT-PCR is performed, but reagents and consumables are running out due to the increase in the number of tests worldwide.
There is a report of how this preprocessing process can be simplified as follows.
https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0243266

As a result, a sample of 20uL to 40uL was heat treated at 95°C to 98°C for 2 to 20 minutes to obtain good RT-PCR results.
The RT-PCR kit evaluated were
ABI TaqMan fast virus 1-Step RT-qPCR kit,
Meridian Bioscience Fast 1-Step RT-qPCR kit.

However, when the sample was suspended using UTM Viral Transport COPAN, this method failed to produce any detectable signal.
The cause is unknown because the composition of the reagent is not disclosed. So, depending on the combination of reagents used in the RT-PCR Kit, it seems that a simplified pre-treatment of heat treatment may not work properly.

Colorectal Cancer and Tn-Antigen

A group from Fukushima Medical University has discussed about a key-point on colorectal cancer immunotherapy based on colorectal cancer and Tn-antigen.
https://www.mdpi.com/1422-0067/21/23/9081

In cancer, mutations are accumulated in the genome and epigenome. In colorectal cancer, 85% are derived from chromosomal instability and 15% from deficient mismatch-repair (dMMR).
It is also well known that in cancer, aberrant glycans are expressed on the cell surface, and O-type glycans are truncated, and resulting Tn-antigens are highly expressed. Tn-antigen binds to macrophage MGL and promotes il-10 secretion and acts immuno-suppressively, as well as inducing T-cell apoptosis. As a result, cancer cells evade immunity attacks.

Cancer cells with deficient mismatch-repair have significantly higher expression of Tn-antigen than those that are not. In addition, those types of cancer cells tend to have less infiltration of CD8+ T-cells and lower expression of PD-L1 as an immune checkpoint molecule. Therefore, they have concluded that immunotherapy targeting on Tn-antigens and inhibition of immune checkpoint molecules may be effective for colorectal cancer with a strong deficient mismatch-repair.

The effects of ACE2 inhibitors in the new coronavirus (COVID-19), Dangerous in Diabetes Mellitus

The new coronavirus (COVID-19) is known to cause serious diseases with underlying disease such as acute kidney disease, diabetes, immunodeficiency, and obstructive airway disease.
Acute renal disease (HR = 3.23, 95% CI: 2.01 to 5.19),
Diabetes (HR = 2.07, 95% CI: 1.32 to 3.26),
Immunodeficiency (HR = 2.33, 95% CI: 1.29 to4.2),
Obstructive airway disease (HR = 2.13, 95 % CI: 1.06 -4.3),

Since ACE2 is the main infection receptor for SARS-CoV-2, the following group has performed statistical analysis based on data obtained from 617 patients on side effects of ACE inhibitors.
http://www.ijkd.org/index.php/ijkd/article/view/5920/1222

Side effects of ACE inhibitors are particularly severe in diabetes (HR = 3.51, 95% CI: 1.59 to 7.75).
In the figure below, DM=Diabetes Mellitus, ACE=0 means no ACE inhibitors, and ACE=1 means with ACE inhibitors.

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