Archive 21/2/9

A group from Osaka University etc. has found that Rab11 (a regulator of membrane vesicle transport via recycling endosomes) is deeply involved in N-glycan modification.
https://www.jbc.org/article/S0021-9258(21)00126-5/fulltext

Glycan modification is controlled by glycosyltransferases present in the endoplasmic reticulum and Golgi bodies. Therefore, if each glycosyltransferase is not in an appropriate position, the glycan modification is not performed correctly. Unfortunately, the mechanism for transporting glycosyltransferases to the correct positions is not known.

The authors have found that Rab11, a regulator of membrane vesicle transport, was heavily involved in the modification of α2-3Sia. In cells that knocked out Rab11, the modification of α2-3Sia was greatly upregulated, and thereby it was found that Rab11 negatively controlled the α2-3Sia modification by transporting the glycosyltransferase ST3GAL4 out of the Golgi body region.

The figure below shows the role of Rab11 in a healthy state.

A group from The Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain etc. has reported that high HDL good cholesterol significantly reduces the risk of covid-19 infection.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852244/

As shown in the figure below, it can be shown that as HDL cholesterol increases, the risk of infection with the new coronavirus (SARS-CoV-2) is reduced monotonically. The statistical analysis was performed with data from 317,306 people. By multiplying 38.66535, mmol/L can be converted to mg/dL.

The new coronavirus (Covid-19) is known to cause a hypercoagulable state such as cardiovascular complications as well as acute respiratory distress syndrome (ARDS).

A group from Technical University of Munich etc. has used antibody panels of 21 membrane-penetrating proteins, to investigate the expression status of those markers in platelets by mass cytometry.
https://www.nature.com/articles/s41419-020-03333-9

From Mass cytometry, it was fount that the expression of P-Selectin (0.67 vs. 1.87 Healthy Median vs. Median COVID-19 patients, p = 0.0015), LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), GPIIb/IIIa complex (4.58 vs. 5.03, p< 0.0001) are upregulated. P-Selectin functions as a cell adhesion molecule on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activates platelets. GPIIb/IIIa is an integrin complex found on platelets, a receptor for fibrinogen and von Willebrand factor, and aids platelet activation。LAMP-3 is one of the lysosome-associated membrane glycoproteins。

The adhesion protein P-Selectin translocates to the plasma membrane upon activation and regulates platelet–leukocyte interactions resulting in activation of neutrophil integrins and inducing NETS formation. NETS is one of functions of innate immunity, and capture and eliminate virus. However, the excess NETS leads to hypercoagulopathy. P-Selectin expression together with the upregulation of the GPIIb/IIIa comples contributes to the COVID-19 inflammatory response. Although the pathophysiological mechanisms behind the high incidence of thromboembolic events in hospitalized COVID-19 patients remain unclear and the key drivers behind platelet activation in COVID-19 remain to be determined, it may be induced by infected endothelium as well as by the cytokine storm occurring during SARS-CoV-2 infection.

Several research institutes have already reported that type O blood is more resistant to SARS-CoV-2 and type A blood is less resistant. This suggests that the presence of anti-A antibodies must be related to SARS-CoV-2 infection protection.
A group from Universe libre de Bruxelles (ULB), Brussels, Belgium, etc. has speculated that the presence of anti-A and anti-B antibodies is a true problem and that it is related to the protective effect against SARS-CoV-2.

https://www.ijidonline.com/article/S1201-9712(20)32549-2/fulltext

Type O: IgM anti-A+ anti-B agglutination score: 88.29±33.01 (healthy people), 76.93±34.93 (COVID-19 patients)
Type A: IgM Anti-B agglutination score: 30.40±18.84 (Healthy), 24.93±18.73 (COVID-19 Patients)
Type B: IgM anti-A agglutination score: 36.50±17.41 (healthy persons), 28.56±17.41 (COVID-19 patients)

From these results, it could be said that as the presence of anti-A antibodies and anti-B antibodies is small, the resistance to SARS-CoV-2 weakens and it becomes easy to become infected, and if the amount of presence is not large, the effect of infection protection due to differences in blood types would not be clear.

Anti-A and anti-B antibodies are synthesized by immune stimulation from gastrointestinal microbiota. Both these antibody production and microbiota vary greatly according to an individual’s age and nutritional status. In other words, the promotion of ABO antibody production by the gastrointestinal microbiota will help prevent the infection of the novel coronavirus! ?

The key question in vaccine development would be, under the selective pressure of the polyclonal immune response of vaccinated people, if the virus evolves to escape from the immunity? and if it is effective against virus mutations or not?

A group from Fondazione Toscana Life Sciences, Siena, Italy etc. has reported the results of co-culture of cells and virus with using neutralize antibodies (polyclonal) obtained from the plasma of convalescent patients from the new coronavirus (COVID-19).
https://pubmed.ncbi.nlm.nih.gov/33398278/

In this experiment, VERO E6 cells and SARS-CoV-2 were co-cultured for 100 days (14 passages over) using neutralizing antibodies with the highest neutralizing titer among 20 convalescent patients, to investigate the relationship between changes in the titer of neutralize antibodies and genetic mutations that occurred in viruses. In this experiment, the following mutations have occurred in the NTD and RBD of the S protein, and it is shown that the titer of the neutralize antibody decreases with it.

1. deletion of the phenylalanine in position 140 (F140) on the S-protein NTD N3 loop.
2. glutamic acid in position 484 of the RBD was substituted with a lysine (E484K).
3. 11-amino-acid insertion between Y248 and L249 in the NTD N5 loop (248aKTRNKSTSRRE248k).

The results of this experiment show that virus can evolve to escape from the selective pressure of even the highest titer neutralize antibodies. So, it is recommended to use cocktail antibodies for treatment. In addition, it suggests the need to develop a second-generation vaccine that can accommodate mutations.

It is known that there are three type of innate immunity, (1)phagocytosis with phagocytic cells such as macrophages and NK cells, (2)complement lectin pathways, and (3)extra-spherical traps . In the complement lectin pathway, Mannose Binding Lectin (MBL) plays a central role, and when MBL binds to the mannose on the pathogen’s cell membrane, an enzyme called MBL-binding serine protease (MASP) bound to MBL is activated, and MASP activates the complement Factor 4 (C4), which sequentially activates the complements and ultimately kills it by drilling a hole in the pathogen’s cell membrane.

A group of Istanbul Faculty of Medicine, Istanbul Univ. has reported that the genetic variants in MBL are largely related to the severity of covid-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838598/

For the mutation of codon52 of the MBL2 gene,
Referring to AA genotype,
BB genotype: odds ratio (OR) = 5.3, p< 0.001;
AB genotype: OR = 2.9, p = 0.001

For the ICU need, the odds ratios get higher as follows,
BB genotype: OR = 19.6, p < 0.001
AB genotype: OR = 6.9, p = 0.001

This could be a good reference in using MBL as a therapeutic protein.