Archive 21/2/20

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.