Month: March 2021

A group from Medical School, Nagoya University has reported that the inhibition of C2GnT (O-glycan Core2 acetylglucosaminyltransferase）would be effective for the treatment of choriocarcinoma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895715/

Choriocarcinoma is a disease specific to women and a malignant tumor produced in placental trophoblasts.

It was thought that cytotoxicity of NK cells is activated through interraction between NKG2D, which is a receptor expressed and on NK cells, and MHC class I-related chain A (MICA), which is often expressed on tumor cells.

As shown in the figures below, it is obvious that MICA is O-glycosylated with a core 2 poly lactosamine elongated structure, because glyco-catched MICA with LEL lectin decreases with C2GnT KO. By knocking out C2GnT, the elongation of core 2 structures with poly lactosamine is prohibited, of course. Jar and BeWo are choriocarcinoma cell lines, and the comparison between control and C2GnT KO cells shows that NK cell cytotoxicity increases with C2GnT KO. And it is also clear that NK cell cytotoxicity is activated by endo-β-galactosidase treatment, because it cut out poly lactosamine structures from core 2 O-glycans.
So, these results indicate that poly lactosamine elongation of core2 O-glycan is inhibiting NK cell cytotoxicity, and therefore, with increasing C2GnT, choriocarcinoma cells could escape from NK cell attacks eventually. This also means that inhibition of C2GnT would be effective for the treatment of choriocarcinoma.

On a blog article posted on May 1st, 2021, it was introduced that the fucosylation of HIV gp120-specific IgG is decreased in some HIV patients.

A group from University of Amsterdam, etc. has indicated that the fucosylation of SARS-CoV-2 S-protein-specific IgG is also decreased in some COVID-19 patients.
https://science.sciencemag.org/content/371/6532/eabc8378.long

It is well known that the effector functions such as ADCC and ADCP are reinforced with afucosylation of IgG Fc. If this moves in a positive direction, it can accelerate virus clearance. This would be exactly true in the case of HIV infection. However, immunity potentially behave as double-edged swords, and in the case of COVID-19, it was thought that afucosylation of IgG might promote the production of pro-inflammatory cytokine IL-6 resulting in cytokine storm and tissue damages.

In the figures below, it is shown that when Acute Respiratory Distress Syndrome (ARDS) is developed, fucosylation of S-protein specific IgG is decreased, although there is no change in fucosylation of total IgG. This means that the effector functions of antibodies are enforced. And further, when afucosylation of IgG proceeds, IL-6 production is accelerated and CRP as an Inflammatory marker gets higher.

A group from Medical School University of Tokyo, etc. has reported on changes in neutralizing antibody titers from sequential blood samples collected from Jan. 2020 to Apr. 2020 in Japan.
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00014-6/fulltext

After the infection onset, it seems that the neutralization titer is maintained for a several months. In the figure below, 95% CI is shown in gray color, and the red line shows the median value. As for the pathogenicity of SARS-CoV-2 via antibody-dependent enhancement (ADE) activity, numerous studies are ongoing in the world. But, no studies describing an increase in pathogenicity due to ADE have been reported yet, so that authors are thinking that the possibility of ADE would be limited.

A blog article about Lactoferrin was already uploaded on Feb. 12th, 2021, focusing on the antiviral function of Lactoferrin. It is know that Heparan sulfate is a co-receptor for SARS-CoV-2 positioning ACE2 as the primary receptor. The antiviral function of lactoferrin is considered to inhibit SARS-CoV-2 binding to heparan sulfate.

A group from Kagawa Nutrition University is recommending to take 2 capsules of enteric lactoferrin (1 capsule = 30mg) purchasable without doctor’s prescription everyday. You could purchase it easily even from Amazon. Actually, Mongolia shows the world lowest fatality rate, and the group pointed out that Mongolians are taking larger amount of lactoferrin than any other nations in the world.
https://www.eiyo.ac.jp/ions/?p=4407  

A group from University of Oxford, etc. has reported quite interesting immune response of HIV infected children.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763548/

There are some asymptomatic children, HIV-infected pediatric nonprogressors (PNPs), who maintain normal CD4 counts HIV despite ongoing viral replication at high rates in the absence of antiretroviral therapy (ATR). It is also very interesting that some children develop broadly neutralizing antibodies (bnAb). It is also characteristic that the effector functions (ADCC and ADCP) mediated by IgG Fc binding to effector cells such as NK cells and macrophages are strong in the PNPs.

As for IgG glycosylation, PNPs have similar glycosylation to health controls, or rather, slightly higher sialylation and lower core fucosylation, although HIV infected adults usually develop agalacto type N-glycans.

It was also found that bnAb collelated with circulating Tfh cells and sialylation of gp120-specific IgG.
It is well know that the effector functions via IgG Fc binding get higher with increasing core fucosylation.

Taking these things into consideration, the immune activation in PNPs is rather low, but it might be compensated by the existence of bnAb and stronger effector functions. 

A group from UC San Diego, etc. has shown that a complex type N-glycan at N343 position controls open and close configurations of SARS-cOv-2 RBD with using a molecular dynamics simulations. It will be clear from the figures below.
https://www.biorxiv.org/content/10.1101/2021.02.15.431212v1
 

A group from Ohio State University Wexner Medical Center, etc. has reported that excess compliments are deposited in Membranous Nephropathy (MN).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879111/pdf/main.pdf

Glomeruli tissue samples were captured by laser microdissection, and IgGs and complements in the samples were analyzed by mass spectrometry comprehensively. As a result, elevated glomerular levels of all complements (except for CR1) and IgG1~IgG4 were observed in MN patients comparing with health controls. On the other hand, mannose-binding lectin (MBL), Ficolin, and Collectin were not detected. These results suggest that Glomeruli tissue could be damaged by excessively activated complements not through the lectin pathway. Loss of CR1 at the site of the damaged filtration barrier might accelerate excess complement activation resulting in significant damages. In addition, it is thought that M-type phospholipase A2 receptor (PLA2R) could be an antigen in membranous nephropathy.

A group from NMI Natural and Medical Sciences Institute at the University of Tübingen, etc. has reported on the cross-reactivity of hCoV-specific IgGs against SARS-CoV-2 infected and uninfected individuals using 1,173 serum/plasma samples.
https://www.nature.com/articles/s41467-021-20973-3.pdf

Up to now, it has been known that there are 4 kinds of epidemic human coronaviruses (hCoVs: NL63, 229E, OC43, HKU1) which cause seasonal colds.
As shown below, there is certainly correlation between SARS-CoV-2 and hCoVs specific IgGs to a certain degree. 10% of SARS-CoV-2 infected individuals do not develop detectable SARS-CoV-2-specific IgG, but it has not been identified if this result could come from cross-reactivity of hCoVs-specific IgGs or just from innate immunity against SARS-CoV-2.

There have been some papers reporting that C-type Lectins could be SARS-CoV-2 infection receptors as well as well-know ACE2.
Harvard Medical School, July 30, 2020
https://www.biorxiv.org/content/10.1101/2020.07.29.227462v1
Boston University, Dec. 9, 2020
https://www.biorxiv.org/content/10.1101/2020.06.22.165803v2
There was a review paper from Boston University, (Dec. 22, 2020) in addition to the above paper, let me introduce two kinds of interesting data for your reference.
https://www.mdpi.com/2079-7737/10/1/1

Although ACE2 is a really important virus receptor, the expression level of ACE in lung is very low, however, CD209 and CD209L are more broadly expressed in human tissues rather than the ACE2.
A result of infection experiments using SAR-CoV-2 pseudotyped lentivirus and HEK293 cells overly expressing CD209L, CD209, and ACE2 is also shown below.
Taking these things into consideration, it would be clear that CD209 and CD209L could mediate SARS-CoV-2 entry as infection receptors even for tissues lacking ACE2 expression.
The CRDs of C-type Lectins (DC-SIGN, L-SIGN) recognize strongly high mannose type glycans.