Category: Nature

In the 2009 N1H1 influenza pandemic, young people, like the new coronavirus, tended to be mild and became more severe as they aged.

The following group, using ferrets as a model, has investigated if any change in glycosylation might be involved in the background relationship between the severity of N1H1 influenza and age? They used lectin microarrays for comparative glycan profiling analysis with using Ferret lungs as samples.
https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00455

As a result
In aged ferrets, high mannose was highly expressed as they became more severe.
In newly weaned ferrets, however, the expression of high mannose increased from 3 to 5 days after the infection, but since then, glycan modification has recovered to the same level as in healthy states, and stayed in mild and recovered.
It can be seen that glycan modification is deeply related to severity of influenza.

When cancer progresses, O-type glycans are truncated and Tn-antigen (α-GalNAc) is highly expressed as a result. However, the relationship between the high expression of Tn-antigens and the proliferation and metastasis of cancer cells has not yet been fully studied.
The following group used a colorectal cancer model in mice (using MC38 cells) to study how Tn-antigen influences its gene expression, by using CRISPR/Cas-9 to create a cell line MC38-Tn(high) that lacks a glycosyltransferase (C1galt1c1) involved in the elongation of Tn-antigen to T-antigen (Galβ1-3GalNAc）.
https://www.frontiersin.org/articles/10.3389/fonc.2020.01622/full

As a result, changes in expression levels occurred in 1,348 genes (with log2 fold change), 641 genes were down regulated, and 707 genes were up regulated.
Comprehensively, signal paths related to antigen presentation and T-cell activation are suppressed, and seems to be changing in the direction of enhancing the growth and metastasis of cancer cells.

RT-PCR is Gold Standard for testing for the new Coronavirus (SARS-CoV-2).

However, you need to be careful about RT-PCR results. Rt-PCR tests from the nasopharyngeal are highly reliable until the fourth day after signs of infection, but after 10 days, the detection accuracy falls and the probability of false negative gets very high.
On the other hand, the test from the feces is not reliable at the beginning of infection, but it is possible to detect the virus even after a number of days of infection, and it is better to use feces than to obtain samples from the nasopharyngeal to determine whether the virus has been eliminated in the end.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01810-8

In this figure, dark blue and dark gray indicate virus detection two weeks before and after infection, respectively, and light blue and light gray indicate false negatives.

The following group has reported the results of a study of cross-antibodies between the new coronavirus (SARS-CoV-2) and coronavirus (HCoVs) that contribute to the seasonal cold.
https://science.sciencemag.org/content/early/2020/11/05/science.abe1107

The HCoVs antibodies seem to have the effect of suppressing SARS-CoV-2 infection with the cross-reactivity for people who have never infected with the new coronavirus.
This cross-antibody is not targeting RBD of SARS-CoV-2 as the epitope, but common amino acid sequences in the S2 region seem to be the ones as shown below.

In addition, since the retention rate of the cross-antibody is high in young people, it may be related to the phenomenon that young people are less likely to develop the severe illness of COVID-19.

When COVID-19 develops and becomes severe with the new coronavirus, cytokines such as IL-6, IL-18, IFN-γ, IL-15, TNF-α, IL-1α, IL-1β are upregulated, and fall into the so-called cytokine storm state. It is widely known that acute respiratory distress syndrome (ARDS) in COVID-19 is directly correlated with this cytokine storm.

In the expression of such various cytokines, it has been pointed out by the following group that the synergetic effects of TNF-α and IFN-γ in particular may be causing severe disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605562/

Here is an example of in vivo experiment using a mouse that the synergetic effect of TNF-α and IFN-γ mimics the symptoms of COVID-19.

It has also verified in vivo that applying TNF-α and IFN-γ neutralizing antibodies to hACE2 transgenic mice infected with SARS-CoV-2 increases survival rates significantly.

So, inhibitors for accurate points in the downstream signal path of including TNF-α and IFN-γ will lead to development of effective drugs for ADRS of COVID-19.

Clinical studies in South Korea have reported statistical analysis of the effects of diabetes on the new coronavirus (COVID-19).
https://e-dmj.org/journal/view.php?doi=10.4093/dmj.2020.0141

The OR (odds ratio: 95% CI) of diabetes statistically calculated by taking into account the effects of age, sex, hypertension, dyslipidemia, chronic kidney disease, chronic obstructive lung disease, cardiovascular disease, atrial fibrillation, end-stage renal disease, cancer on COVID-19 was as follows:

Hospitalization: 1.071 (0.722 – 1.588)
Oxygen inhalation: 1.349 (1.099 – 1.656)
Ventilators: 1.930 (1.276 – 2.915)
Death: 2.659 (1.896 – 3.729)

Hydroxychloroquine is one of the candidates for the treatment of the new coronavirus (covid-19). This drug is said to prevent the proliferation of the virus by inhibiting RNA polymerase.
As for the mechanism of this medicine, by opening a gate on the cell membrane so that zinc ions can enter into the cell, and the zinc inhibits the function of RNA polymerase.

For the new coronavirus, the effect of this hydroxychloroquine was investigated by comparing the administrated group with the non-administered group. As an evaluation index in this study, the amount of the new coronavirus was evaluated with the number of cycles (Ct) to reach the PCR reaction threshold in RT-PCR.
Unfortunately, it turned out that there was not a significant difference between the two groups.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592126/

Over the past days, the mechanism is different from Hydroxychloroquine, but the WHO has announced that Remdesivir, which also inhibits the proliferation of virus, was not effetive.
More and more, the battle against coronavirus is not in sight.

In the new coronavirus, it is well known that ACE2 is the main receptor. The results of a detailed investigation of the expression status of ACE2 in human have been reported.
https://www.nature.com/articles/s41467-020-19145-6

Ace2 is said to be expressed in the nasopharynx, lungs, small intestine, kidneys, and testes by gene expression analysis, but immunostaining using ACE2 antibodies shows that ACE2 is relatively less expressed in the lungs than in other organs. In addition, ACE2 seems to be expressed in a fairly locally expressed in motile cilia on epithelial cells of the Upper respiratory tract.

On the other hand, it was also found that the expression level of ACE2 was little correlated with age, gender, and smoking. The administration of drugs such as Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) used in the treatment of hypertension, which is a concern for SARS-CoV-2 infections, was also found to have no effect on ACE2 expression.

Therefore, as for the prevention and severity of the new coronavirus (COVID-19), the followings are pointed out as a conclusion.
(1) SARS-CoV-2 inhibitors in the oral nasal cavity are effective in preventing infection,
(2) The expression level of ACE2 itself has nothing to do with the severity of COVID-19.

For influenza viruses, it is well known that the binding of α2-6Sia in human respiratory tract cells and HA (hemaggulutinin) with influenza virus causes infection. However, the relationship between the severity of influenza and the glycosylation is not well known.
The following groups use lectin microarrays to study the severity of influenza and the glycosylation of Host Cells using ferret model.
https://www.pnas.org/content/117/43/26926.long

The result is that the glycosylation of Host cells changes when infected with the influenza virus, and the increase in the high mannose structure is correlated with the severity of the disease.
This is an interesting phenomenon. The high Mannose-binding C-type lectin is expressed on immune cells, so its association resulting in self-tissue damages might be suspected.

The fact that the S-protein sequence of the new coronavirus (SARS-CoV-2) contains an unique sequence “PRRA” not found in other coronaviruses is inserted at the boundary between the S1 and S2 domains. It has also been frequently pointed out that the presence of this sequence has increased the infectivity of this virus to humans.

There is a paper discussing about the presence of a staphylococcal enterotoxin-like sequence around the inserted “PRRA” sequence (661-685) of SARS-CoV-2, and its potential effect on hyperinflammation of COVID-19.
https://www.pnas.org/content/117/41/25254.long

By binding the T cell receptors (TCR) to this bacterial toxin-like sequence, the resulting toxic shock syndrome might be behind of the severe hyperinflammation of COVID-19? It says. This inference was made from molecular structural analysis of proteins, and is expected to be tested in practice.

SEB represents staphylococcal enterotoxin and has a quite structure similar to the 661-685 sequence of SARS-CoV-2.