Year: 2020

The fact that the new coronavirus (COVID-19) is more likely to develop severe respiratory illness with the age is well known. This behavior is not specific to COVID-19 and shows a similar trend also in SARS and MARS that have occurred in the past.
Below is the result of the latest COVID-19 fatality rates by ten-year age-groups in seven countries.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241031

The figure above proves splendidly that the elderly persons are really dangerous. But why does the fatality rate increase as the age increases? Unfortunately, we still don’t know exactly what the mechanism is for this.

However, generally speaking, when the age increases, (1) dendritic cells and alveolar macrophages decrease, (2) the expression level of TLR7 and MDA5 is reduced, which are virus RNA receptors to activate innate immunity, and (3) although neutrophils and alveolar macrophages are on the increase, it can be said that the immune function of these cells such as phagocytosis etc. tends to decrease with the age. In other words, it seems to be a rough picture that the impaired innate and adaptive immune responses develops severe disease.
https://www.jci.org/articles/view/144115

A group of University of Bologna has evaluated the effects of ABO blood types on the risk of infection with the new coronavirus (COVID-19) using 7,503 cases and 296,216 controls.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500631/

The reported results are as follows,

Type A: OR: 1.23 (95% CI: 1.09-1.4)
Type B: OR: 1,05 (95% CI: 0.96-1.15)
AB Type: OR: 1.09 (95% CI: 0.94-1.26)
Type O: OR: 0.77 (95% CI: 0.67-0.88)

Further, a group of Sakarya University has reported that the Rh+ blood group was found in a significantly high number of patients who were admitted to ICU.
https://pubmed.ncbi.nlm.nih.gov/32965363/

A group of Harvard medical school reported about why the humoral response (antibody-centric adaptive immune response) is non-persistent in the new coronavirus (COVID-19)?
https://pubmed.ncbi.nlm.nih.gov/32877699/

In addition to innate immunity, adaptive immunity centered on antibodies plays an important role in the elimination of foreign substances such as viruses that invade the living body. In the early stages of infection, low affinity IgG antibodies are produced, but IgG antibodies produced over time mature and increase affinity for antigens. This is because B cells that produce high affinity antibodies differentiate in germinal center (a small structure formed in the immune system, such as the spleen and lymph nodes, during the immune response). In the early stages of infection, antigen-specific B cells quickly differentiate into plasma cells to produce low-affinity antibodies, but some B cells express transcription factor Bcl6 (Bcl-6 Tfh cells) to form the germinal center.

In fact, in COVID-19, the fact that the formation of this germinal center is suppressed seems to be the cause of the title. Why is the formation of the cup center suppressed? The detailed mechanism is not known, however,  it is said that excessive production of cytokines such as TNF-α suppresses the differentiation of Bcl6-Tfh cells and results in loss of germinal center.

This behavior seems to occur not only in COPID-19, but also in Ebora, Marburg disease, and H5N1 influenza.

Glycans, as is said to be the face of cells, greatly change the structure depending on the state of the cell. It is known that specific changes in the glycan structure occur in canceration, and various diagnostic and therapeutic drugs are under development using glycans as the drug discovery targets. Changes in glycan structure caused by canceration depend on the type of cancer, but common characteristics include followings:

(1) Increase in multi-branching of N-type sugar chains
(2) Shortening of O-type glycan chains
(3) Increase in terminal-sialic acid modification
https://jitc.bmj.com/content/8/2/e001222.long

However, in addition to these, there seems to be a feature that the amount of glycan modification increases when it becomes cancerous, and the high mannose structure increases, too.
https://pubmed.ncbi.nlm.nih.gov/32143591/

Based on the cited papers above, I will summarize the strategy of glycan targeted drug discovery as follows.

• Antobody-drug conjugates (ADC): target on cancerous cell surface expressing targeted glycans using glycan binding agents (i.e., lectins etc.). In this case, it might work better to adopt bispecific antibodies to glycans on target cancerous cell surface more precisely  (e.g., bispecific to GD2 ganglioside and MUC1)
• Siglec inhibitors: Siglec is expressed on most of the immune cells, the immune response is suppressed when the signal is triggered by binding to sialoglycan.
• Galectin inhibitors: tumor cells highly express galectins, and bind to immune checkpoint CTLA-4 to suppress the immune response. Galectin-1 induces apoptosis of T- cells.
• Immune checkpoint inhibitors: PD-1/PD-L1 are also strongly glycosylated, and molecular-targeted drugs with those excellent inhibitory effects are promising.
• C-type lectins: DC-SIGN, Dectin-1 and others promote anti-tumor activity, while NK62DG and Mincle work immuno-suppressively

A group of Chulalongkorn Univ. reported the IgG response of patients with the new coronavirus (COVID-19) in Thailand as follows:
The study is based on data from 384 patients analyzed between March 10 and May 31, 2020.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240502

IgG in serum comes up two weeks after infection.
In patients with mild infection, IgG was not detected in 20% of patients 2 weeks after infection.
The expression level of IgG increases as mild, moderate, severe and symptoms become heavier.
Men have higher expression of IgG than women.

The reported tendency on IgG correlates with other reports published.

From the RNA sequence of the new coronavirus (SARS-CoV-2) registered from India in NCBI-Virus-database as of June 6, 2020, a research result has been reported on what mutations occurred compared to the original strain that began to spread in Wuhan, China.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521409/

There are 25 mutations, and they are divided into four clusters (1-100, 148-255, 570-680, 820-930).

Mutations in T572I, A879S, A892V, and A930V have caused significant changes in the secondary structure of proteins, T572I causes a structural change to coilded→helix and the other three to helix→beta sheet. Mutations in the A930V, D614G, A706S, and A879S seem to make a relatively large difference in protein structure. Of particular interest is that the mutation of D614G occurs in 88% of RNA sequences, which is a mainstream among new coronaviruses that are spreading in India. For the D614G, it is reported that it promotes the open conformation of RBD, and as a result, the infectivity of the new coronavirus is increased.

R408I, E471Q is said to be a mutation that is seen only in India.

It is well known that the diagnosis for the new coronavirus is twofold; RT-PCR to check for the infection and antibody testing to check for the infection history.
Antibody testing can not be used for early diagnosis of SARS-CoV-2, because it take more than a week before the antibody rises up. However, by focusing on serum nucleocapsid protein of SARS-CoV-2, it seems that the infection of the new coronavirus can be detected even early before the antibody (IgG) rises up.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498565/

The ROC curve showed that AUC was 0.9756 (95% CI), sensitivity was 92%, and specificity was 96.8%. The cut-off value of the capsid protein was 1.85 pg/mL.

Wouldn’t it be a great achievement?

As a treatment for the new coronavirus (COVID-19), the usefulness of the fusion protein (RTAM-PAP1) between a mutant of the lysine A chain extracted from Ricinus communis (RTAM) and a lectin extracted from the leaves of Phytolacca americana (PAP1) is reported from the viewpoint of affinity evaluation between various proteins of SARS-CoV-2 and RTAM-PAP1 and also from toxicity testing using mice.
https://www.mdpi.com/2072-6651/12/9/602/htm

The binding affinity between a patient-derived antibody B38 of SARS-CoV-2 (as a control), ACE2, RTAM-PAP1 and various proteins of SARS-CoV-2 were evaluated using three-dimensional molecular structure analysis software named CoDockPP, HASSOCK2.2, and ZDOCK. The binding of RTAM-PAP1 was stronger than ACE2, and showed the same binding affinity as B38 comprehensively.
In addition, the toxicity tests using mice showed no side effects even at 1 mg/kg of dose.

This paper shows the usefulness of the fusion protein of lectins derived from Ricinus communis and Phytolacca americana as a novel drug for the new coronavirus.

Ricinus communis

Phytolacca americana