Category: Nature

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.

What I am always thinking about COVID-19 was written in the following paper published from a group of Central University of Tamil Nadu etc.
https://academic.oup.com/femspd/article/79/1/ftaa076/6027506

In the case of COVID-19, there are so many asymptomatic individuals (some studies have estimated that up to 80%).
Generally speaking, the incubation period for COVID-19 is reported to be between 5 to 6 days, although this can be up to around 14 days, but, asymptomatic individuals show an extended median duration time of 19 days.

SARS-CoV-2 activates the STING pathway and NLRP3 inflammasome assembling, and induces cytokine storm as a result of excess production of IL-1β, and IL-18, TNF-α, IFN-γ, IL-6, etc. However, bats do not develop any disease, although they are reservoir of various viruses. In the case of bats, they are coexisting with virus preparing the following features evolutionally.
(1)limiting the assembly of the NLR family pyrin domain containing three (NLRP3) in monocytes、
(2)loss of the ability to effectively sense exogenic cytoplasmic DNA via loss of PYHIN genes
(3)excessively high levels of the anti-inflammatory cytokine IL-10,
(4)lack of functional killer cell Ig-like (KIR) and killer cell lectin-like (KLR) receptors.

It is know that the levels of inflammatory cytokines are relatively low, and the SARS-CoV-2-specific IgG and neutralizing antibody levels are significantly lower in asymptomatic individuals. This might mean that asymptomatic is a result of weak immune response. And on the contrary, it might be a result of existing antibody cross-reactivity of classical seasonal cold-causing coronaviruses 229E, HKU1, OC43 and NL63.

In the context of coexistence with virus, mechanisms uncovered in bats likely hint the development of therapeutic strategies against COVID-19 in humans. That could be a wisdom, to survive virus wars.
 

Agalacto type complex N-glycans without terminal Gal are often seen in autoimmune disease. Well known Lectins with glycan binding specificity to agalacto are BLL, PVL, GSL-II as shown below. BLL and PVL are mushroom derived, and GSL-II is bean derived.

Boletopsis leucomelaena: BLL lectin

Psathyrella velutina: PVL lectin

Griffonia simplicifolia: GSL-II lectin

A group from New England Biolabs, Inc. has identified gene sequence of Boletopsis grisea, a close North American relative of Boletopsis leucomelaena, and investigated glycan binding specificities of recombinant lectin (named rBGL) with using glycan arrays. Curiously, rBGL has bi-specific glycan binding characteristics, not only to agalacto type N-glycans but also to O-glycans with Thomsen–Friedenreich antigen (TF-antigen; Galβ1,3GalNAc-α-). Depending on applications, the binding specificity to O-glycan would be interesting.
https://www.nature.com/articles/s41598-020-80488-7

A group from Brown University, etc. has reported that Chitinase 3-like-1 (CHI3L1/YKL-40) could be a good therapeutic target for the new coronavirus (COVID-19).
https://pubmed.ncbi.nlm.nih.gov/33442679/

In the case of COVID-19, majority is asymptomatic or mild, but 10-20% of patients require hospitalization. Especially, it is so interesting that the severity of COVID-19 is deeply related to aging and comorbid disorders (such as diabetes, hypertension, obesity and metabolic syndrome, cardiovascular disease and chronic lung diseases like COPD and asthma). It is know that CHI3L1 is secreted from a spectrum of cells in response to a variety of injury and inflammation, and regulates innate and adaptive immunity and also protects apoptosis. What’s even more interesting is that CHI3L1 increases with aging and also with risk factors of COVID-19 (i.e., presence of comorbid disorders). Taking these things into consideration, authors focused on the relationship between CHI3L1 and angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), cathepsin L (CTSL).

In an in vivo experiment using mice, it was found that CHI3L1 stimulates expression of pulmonary ACE2, TMPRSS2, and CTSL. In other experiments using Calu-3 lung epithelial cells, the expression of ACE2, TMPRSS2, CTSL increased monotonically with CHI3L1 dose, and also it was found that a monoclonal antibody for CHI3L1 (FRG) strongly inhibits the expression of ACE2, TMPRSS2, and CTSL. In actual COVID-19 patients hospitalized, it was also indicated that there is a significant correlation between severity and CHI3L1.

These evidences suggest strongly that CHI3L1 could be a good therapeutic target for COVID-19. Let’s anticipate the future research. 

A group from University de Monterey, etc. has reported an evaluation result of SARS-CoV-2 neutralization activities of IgM, IgA, and IgG using plasma samples from 25 convalescent patients with the new coronavirus (COVID-19).
https://pubmed.ncbi.nlm.nih.gov/33596407/

IgM, IgA, and IgG were selectively depleted using isotype-specific ligands immobilized on beads, respectively. A comparison of the SARS-CoV-2 pseudoviral inhibitory dilution (ID50) for each plasma is shown below. In the IgM-depleted plasma, neutralization activity was greatly reduced by 5.5 times, the secondary one was the IgG-depleted plasma with the reduction of 4.5 times, and the reduction of IgA-depleted plasma was 2.4 times. Considering that IgM is only 5% of total immunoglobulin, the neutralization activity of IgM is very curious.

A group from University of Bern, Switzerland, etc. has reported a sharp increase of Q677 mutations (Q677H and Q677P) in clade 20G (lineage B.1.2) of the new coronavirus (SARS-CoV-2) in the USA. Since this mutation is present in the proximity of the furin cleavage site, it may have an effect on infectivity, but detailed research will be a future issue.
https://pubmed.ncbi.nlm.nih.gov/33594385/

A group from Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, etc. has reported excessive complement activation in kidneys of patients with the new coronavirus (COVID-19).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878379/

COVID-19 causes severe acute respiratory syndrome (ARDS), and the tissue damage is not restricted to lungs but also develop cardiac and kidney injury. In the case of kidneys, the glomerules and tubules seem to be damaged. Excessive activation of complements develops excessive membrane attack complex (MAC) resulting in damage of the glomerular and tubular tissues.
The table below shows a comparison of the level of complement expression among COVID-19 and typical kidney diseases comparing with a control.

ATI: acute tubular injury
HUS: hemolytic uremic syndrome
DIC: disseminated intravascular coagulation

A group from University of Melbourne, etc. has investigated changes in glycan modification in myogenesis over time, while studying the functions of Galectins.
https://www.mcponline.org/article/S1535-9476(20)35144-6/fulltext

In myogenesis, there was a tendency that terminal di-Gal modification down regulated, α2-6Sia modification up regulated, α2-3Sia modification down regulated inversely, and paucimannose up regulated. These changes were thought to be related to intercellular signaling in myogenesis, but the specific signal paths were still unknown. On the other hand, as for galectins, the expression of Galectin-1 increased and the expression of Galectin-3 decreased.
Using newborn mice, an empty multiple cloning site (MCS) was injected with AAV6 into the left foot (as a control), and a galectin-1 gene (LGALS1) was injected with AAV6 into the right foot, and the difference between them was compared after 42 days. it was found that muscle mass was significantly increased with the injection of LGALS1. So, it is clear that galectin-1 is able to promote muscle development.
In the figure below, 14-3-3 protein was referenced as a comparison of LGALS1. 14-3-3 protein is related to intercellular signaling, and recognizes Ser/Thr residues in a specific domain of target protein with a phosphorylation-dependent way, and extracts the physiological function of the phosphorylation state.

A group of NIH has reported the effects of O-glycan modification around the furin cleavage site of the new coronavirus (SARS-CoV-2) to the increased infectivity of the UK variant (B.1.1.7).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872346/

At the S1/S2 boundary of SARS-CoV-2 S-protein, an unique sequence of 4 amino acids (PRRA) is inserted forming the furin cleavage site as shown below.

S673, T676 are the positions where O-glycans are modified, as shown above. The presence of proline at 681 was deeply related to O-glycan modification at those positions. The authors also found that GALNT1 is the most active one glycosylating the furin proximal region among glycosyltransferase GALNT family. Furthermore, addition of O-glycans was shown to significantly suppress the cleavage at the furin cleavage site into S1 and S2. The UK variant (B.1.1.7) has a mutation called P681H, which replaces proline with histidine. Based on the above mentioned results, it is inferred that the non-presence of proline at 681 in UK variant suppresses O-glycan modification, resulting in increased cleavage efficiency and increased infectability.

A group from Juntendo University etc. has found antibodies (IgG) against the S-protein of the new coronavirus (SARS-CoV-2) from bovine milk whey.

https://www.sciencedirect.com/science/article/pii/S0958694621000303?via%3Dihub

The bovine milk was prepared from New Zealand cows in November 2018 and August 2019, and they discovered the presence of IgG for RBD present in the S-protein of SARS-CoV-2 from the bovine milk whey. The genome sequence of the S-protein is shown below, and the epitope mapping of the IgG shows that RBD is the one. Therefore, IgG enriched from milk whey may show neutralize activity against SARS-CoV-2.
However, this bovine milk whey was milked before the spread of COVID-19, and it is difficult to think that the cows were infected with SARS-CoV-2, and it might have been infected with an unknown coronavirus that shares immunogenicity of SRAS-CoV-2.