The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be much more severe among elderly people. The reasons are unclear. Now, an intriguing preprint research paper on the bioRxiv* server 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 news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
What is CH13L1?
The 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.
This enzyme 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.
Study details
The researchers 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. They tested these findings in genetically engineered mice, as well as in vitro, and in humans.
In mouse studies, the researchers 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). Thus, 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.
Higher CH13L1 in severely or chronically ill patients
In 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. 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.
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
Normally, 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.
What are the implications?
The 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 researchers 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.
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, as well as in treating infected subjects in combination with remdesivir.
Another promising compound is kasugamycin, 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.
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.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- Apr 3 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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