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BREAKING NEWS
Source: COVID-19 Latest  Jan 08, 2021  11 months ago
COVID-19 Latest: American And Japanese Scientists Identify Human Enzyme CHI3L1 As Driving Force Behind Severity In Elderly COVID-19 Patients
COVID-19 Latest: American And Japanese Scientists Identify Human Enzyme CHI3L1 As Driving Force Behind Severity In Elderly COVID-19 Patients
Source: COVID-19 Latest  Jan 08, 2021  11 months ago
COVID-19 Latest: Researchers from Brown University-Rhode Island, U.S., Yale University School of Medicine-U.S. and Kurume University School of Medicine-Japan have in a new study identified a human host enzyme called chitinase 3-like-1 (CHI3L1) as playing a critical role in the progression to disease severity of elderly COVID-19 patients.


 
COVID-19 is caused by the SARS-CoV-2 (SC2) coronavirus and is more prevalent and severe in the elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated.
 
The study team demonstrated that CHI3L1 is a potent stimulator of the SC2 receptor ACE2 and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging and that anti-CHI3L1, kasugamycin and inhibitors of phosphorylation, abrogate these ACE2- and SPP- inductive events.
 
Human studies also demonstrated that the levels of circulating CHI3L1 are increased in the elderly and patients with CM where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP; that this induction is a major mechanism contributing to the effects of aging during SC2 infection and that CHI3L1 coopts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.
 
The study findings were published on a preprint server and are currently being
peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.05.425478v1
 
The COVID-19 disease is known to be much more severe among elderly people but to date the reasons are unclear. The study team reports the identification of an enzyme called chitinase 3-like-1 (CHI3L1) that mediates this age-dependent impact of the virus and could serve as a powerful therapeutic approach in mitigating the severity of COVID-19 in this high-risk group.
 
This enzyme CH13L1 is a conserved 18 glycosyl hydrolase gene family member, produced by many types of cells during times of injury or exposure to stimulatory cytokines. It is important in triggering an essential injury-inflammatory response pathway, modulating both types of immunity, and promoting healing while protecting the body against excessive damage during the course of the inflammatory response. This latter action is mediated by its inhibition of programmed cell death and enhanced wound healing processes such as proliferation and fibrosis.
 
CHI3L1  is found in both normal tissue and, at higher levels, in tissues that are undergoing inflammation, injury, repair, or remodeling. It is especially high in older people, as well as in those with comorbidities such as heart disease, vascular disease, diabetes and other conditions known to pose an increased risk for COVID-19. Along with the angiotensin-converting enzyme 2 (ACE2) that acts as the host cell receptor for SARS-CoV-2, CH13L1 protects the lung against injury.
 
The study team in the current study, therefore, explored the postulate that CH13L1 induces a higher level of ACE2 expression as part of the repair process and that the virus hijacks this pathway to promote its entry into the host tissues.
 
The team tested these findings in genetically engineered mice, as well as in vitro, and in humans.
 
Interestingly in mouse studies, the study team found that the overexpression of CH13L1 led to high levels of ACE2 and TMPRSS2 in the lungs. The ACE2 molecules were localized mostly to the airway epithelium, along with TMPRSS2, but also within the alveoli and blood vessels (both endothelium and smooth muscle).  
 
Hence this enzyme may be central to the lung and systemic injury caused by SARS-CoV-2, at least in part by its effect on vascular smooth muscle and endothelial cells.
 
Significantly vitro experiments with recombinant CH13L1 (rCH13L1) demonstrated significant increases in the levels of mRNAs that encoded both ACE2 and TMPRSS2 in cell lines derived from human lung epithelium, primary human small airway epithelium, and lung fibroblasts.
 
Also when treated with monoclonal anti-CH13L1 antibodies such as FRG, for instance, or other CH13L1 inhibitors, both basal and stimulated levels of ACE2 were reduced, in tandem with CH13L1 activity.
 
It was found that in human cohorts, circulating CH13L1 levels were higher in COVID-19 patients in the emergency department (ED) as well as those with comorbidities. Within the ED group, the levels of this enzyme were higher in the elderly, had hypertensive or other chronic illnesses, or who required oxygen.
 
In normal circumstances, RNA viruses are expected in many cases to activate the RIG-like helicase (RLH) innate immune pathway, which triggers a type I interferon (IFN)-based antiviral immune response. This RLH pathway is crucial in viral clearance but also inhibits CH13L1 expression.
 
However, SARS-CoV-2 acts differently, without inducing type I interferons, thus strategically suppressing the immune response, allowing the virus to infect more cells and spread more rapidly to other hosts, causing more severe disease.
 
The study findings suggest that, indeed, CH13L1 powerfully stimulates ACE2 expression within vascular and lung epithelial cells. ACE2 is also expressed at higher levels in aging tissues, in response to CH13L1, in mice. Thirdly, they found that they could inhibit ACE2 expression by suppressing CH13L1 activity and could block viral infection.
 
Finally, in humans, blood levels of CH13L1 are higher in elderly patients with COVID-19, or those with comorbidities, or with severe COVID-19.
 
The study team demonstrated that COVID-19 severity in the elderly or sick is driven by high levels of CH13L1, as part of the healing and repair process in the host. This response, however, backfires by allowing the virus to infect host cells more readily, agreeing with the observation that viral loads are higher in the aged and those with these comorbidities.
 
Measuring the level of CH13L1 in the circulation could help predict the severity of COVID-19 and the need for hospitalization, though more research will be needed to validate this hypothesis.
 
Importantly more rapid and widespread infection leads to more significant tissue damage, resulting in more severe disease and a greater likelihood of a fatal outcome. The findings also indicate that this enzyme is key to the pathogenesis of COVID-19, making it a prime target for therapeutic development. For instance, FRG could be useful in preventing infection following exposure.
 
Kasugamycin is another promising compound and is an antifungal isolated from Streptomyces kasugaensis. It has been shown also to inhibit the flu virus, among other viruses. It has been used as a human and agricultural antibiotic with an excellent safety record. The current experiment demonstrated it to be a potent CH13L1 inhibitor, preventing the expected rise in ACE2 levels in epithelial cells.
 
It has been found that Kasugamycin also inhibits type 2 immune responses and prevents pathological fibrotic processes, all of which make it a potentially useful and safe drug in COVID-19 prophylaxis and therapy. The CH13L1 phosphorylation inhibitor flavopiridol may also be useful in this respect.
 
For more COVID-19 Latest Updates, keep on logging to Thailand Medical News.
 

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