Host Chitinase 3-like-1 is a universal therapeutic target for SARS-CoV-2 viral variants in COVID-19

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Abstract

COVID-19 is the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2; SC2) which has caused a world-wide pandemic with striking morbidity and mortality. Evaluation of SC2 strains demonstrated impressive genetic variability and many of these viral variants are now defined as variants of concern (VOC) that cause enhanced transmissibility, decreased susceptibility to antibody neutralization or therapeutics and or the ability to induce severe disease. Currently, the delta (d) and omicron (o) variants are particularly problematic based on their impressive and unprecedented transmissibility and ability to cause break through infections. The delta variant also accumulates at high concentrations in host tissues and has caused waves of lethal disease. Because studies from our laboratory have demonstrated that chitinase 3-like-1 (CHI3L1) stimulates ACE2 and Spike (S) priming proteases that mediate SC2 infection, studies were undertaken to determine if interventions that target CHI3L1 are effective inhibitors of SC2 viral variant infection. Here we demonstrate that CHI3L1 augments epithelial cell infection by pseudoviruses that express the alpha, beta, gamma, delta or omicron S proteins and that the CHI3L1 inhibitors anti-CHI3L1 and kasugamycin inhibit epithelial cell infection by these VOC pseudovirus moieties. Thus, CHI3L1 is a universal, VOC-independent therapeutic target in COVID-19.

Data availability

Figure 3-source data. Immunocytochemical evaluation of delta pseudovirus infection of Calu-3 cells (with FRG Ab Tx).Figure 6-source data. Immunocytotochemical evaluation of delta pseudovirus infection of Calu-3 cells (with Kasugamycin Tx) .Uncut original gel photos of Western blots used in Figures 4A and 4B have been provided as a supporting document.

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Author details

Suchitra Kamle

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.
Bing Ma

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.
Chang Min Lee

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.
Gail Schor

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.
Yang Zhou

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.
Chun Geun Lee

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-9514-3658
Jack A Elias

Department of Molecular Microbiology and Immunology, Brown University, Providence, United States

For correspondence
Jack_elias@brown.edu

Competing interests
Jack A Elias, is a cofounder of Elkurt Pharmaceuticals and Ocean Biomedical which develop therapeutics based on the 18 glycosyl hydrolase gene family.

"This ORCID iD identifies the author of this article:" 0000-0002-3124-8557

Funding

Brown University (Research Seed Grant,GR300201)

Chun Geun Lee

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.