Host Chitinase 3-like-1 is a universal therapeutic target for SARS-CoV-2 viral variants in COVID-19
- Brown University, United States
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.
Article and author information
Author details
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.
Reviewing Editor
- Paul W Noble, Cedars-Sinai Medical Centre, United States
Version history
- Preprint posted: January 24, 2022 (view preprint)
- Received: March 1, 2022
- Accepted: June 19, 2022
- Accepted Manuscript published: June 23, 2022 (version 1)
- Version of Record published: July 11, 2022 (version 2)
Copyright
© 2022, Kamle et al.
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.
Metrics
-
- 535
- views
-
- 172
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Host Chitinase 3-like-1 is a universal therapeutic target for SARS-CoV-2 viral variants in COVID-19
eLife 11:e78273.
https://doi.org/10.7554/eLife.78273
Further reading
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
Systematically tracking and analysing reproductive loss in livestock helps with efforts to safeguard the health and productivity of food animals by identifying causes and high-risk areas.
-
- Microbiology and Infectious Disease
Survival of Mycobacterium tuberculosis within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3′,5′-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including M. tuberculosis. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of rv0805 PDE, and absence of phoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.
