Scientists at Brown University have described the cellular and molecular events that explain why certain groups have a higher risk of COVID-19 infection as well as the risk of severe side effects and death. These populations include the elderly and patients with preexisting medical conditions including diabetes, hypertension, obesity, metabolic syndrome, cardiovascular disease, and chronic lung diseases like COPD and asthma.

The team published its study (“Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19”) in JCI Insight.

“COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in 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. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (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,” the investigators wrote.

“Human studies also demonstrate 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 co-opts 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.”

“This paper details a major discovery in COVID-19,” said corresponding author Jack A. Elias, MD, an immunologist and dean of medicine and biological sciences at Brown. “It shows that levels of a protein called chitinase 3-like-1 increase with age as well as co-morbid diseases and infection. What’s more, chitinase 3-like-1 augments SARS CoV-2 infection.”

Implications for therapeutic development

The findings not only answer important questions about key mechanisms of the complex SARS-CoV-2 virus, Elias said, but also have direct implications for the development of therapeutics to control the viral infection.

Elias is part of a National Institutes of Health-funded laboratory that focuses on the cell and molecular biology of lung injury and repair. Researchers in the lab, including lead study author Suchitra Kamle, PhD, and co-author Chun Geun Lee, PhD, have recently focused on the biology of enzymes and enzyme-like molecules, called chitinases and chitinase-like proteins, respectively. Of particular interest is a chitinase-like protein referred to as chitinase 3-like-1, a molecule naturally found in blood.

“We’ve been studying this gene family here at Brown for a while and we know that it has a large number of biologic effects, as well as tremendously important roles in both health and diseases,” said Lee, a professor (research) of molecular microbiology and immunology.

Chitinase 3-like-1 is the cornerstone of a critical pathway that is activated during injury and inflammation. These researchers and others have shown that circulating levels of chitinase 3-like-1 increase during infection, especially in diseases characterized by inflammation and tissue alterations—like emphysema, asthma, and COPD, some of the same co-morbid diseases that are risk factors for COVID-19.

Lee noted that levels of chitinase 3-like-1 have also been shown to increase during normal aging. In fact, they have been reported to be the best predictor of all-cause mortality in people in their eighties.

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The researchers thought they might be able to take some of the work they’ve already done with this gene family and apply it to COVID-19, according to Elias. They decided to examine the relationship between chitinase 3-like-1 and the receptor ACE2, the spike protein to which the SARS-CoV-2 binds to enter human cells.

In a series of studies, the researchers compared the effects of chitinase 3-like-1 on ACE2 as well as on other protease enzymes that metabolize the spike protein and contribute to infection. They examined these interactions in the lungs of mice that were genetically modified to have exaggerated levels of chitinase 3-like-1 as well as mice deficient in chitinase 3-like-1. In the lab, Kamle led experiments that examined the effects of chitinase 3-like-1 on human lung epithelial cells.

The researchers found that levels of chitinase 3-like-1 increased with age, co-morbid diseases, and infection. In addition, they noted that chitinase 3-like-1 was a potent stimulator of the receptor that SARS-CoV-2 uses to infect cells.

The researchers then developed a humanized monoclonal antibody called FRG that attacks a particular region of chitinase 3-like-1—a step that turned out to be critical. They found that this therapeutic antibody, as well as another small molecule, powerfully blocked the induction of the ACE2 receptor.

“So in that way, the virus cannot enter into the host system,” said Kamle, a Brown investigator in molecular microbiology and immunology as well as antibody engineering. “This means there will be less infection in the presence of this therapeutic FRG antibody.”

These findings could pave the way for the development of therapeutics to protect people from infection, added Elias.

“You can imagine a scenario in which someone who has been exposed to a person who has the virus is given the antibody, which then acts like a prophylactic to prevent infection or make the symptoms that the infection induces milder,” he said.

Elias described another potential scenario in which the person who has the virus is given the antibody or the small molecule, which halts the infection and effectively “cures” the illness.

“We show in this paper that if we make antibodies or other small molecules that can inhibit chitinase 3-like-1, they can be therapeutics to control viral infection,” Elias explained.

The team is currently looking at how these antibodies and small molecules react with different variants of the SARS CoV-2 virus, including the infectious delta variant that has recently changed the course of the pandemic.

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