Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19
Suchitra Kamle, … , Chun Geun Lee, Jack A. Elias
Suchitra Kamle, … , Chun Geun Lee, Jack A. Elias
Published November 8, 2021
Citation Information: JCI Insight. 2021;6(21):e148749. https://doi.org/10.1172/jci.insight.148749.
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Research Article COVID-19 Therapeutics

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19

Abstract

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. 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.

Authors

Suchitra Kamle, Bing Ma, Chuan Hua He, Bedia Akosman, Yang Zhou, Chang-Min Lee, Wafik S. El-Deiry, Kelsey Huntington, Olin Liang, Jason T. Machan, Min-Jong Kang, Hyeon Jun Shin, Emiko Mizoguchi, Chun Geun Lee, Jack A. Elias

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Figure 4

Alterations in CHI3L1 phosphorylation modify its ability to regulate ACE2 and SPP.

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Alterations in CHI3L1 phosphorylation modify its ability to regulate ACE...
(A) Demonstration that CHI3L1 is a phosphoprotein. Biologically active rCHI3L1 was treated with protein phosphatase 2A (PP2A) in the presence and absence of the PP2A inhibitor Okadaic acid. The alterations in CHI3L1 phosphorylation were evaluated with immunoblots using antibodies against phosphoserine or CHI3L1 controls. (B) Calu-3 cells were stimulated with a WT or a mutant form of rCHI3L1 (250 ng/mL for each; 24 hours) that could not be phosphorylated. The latter was done by generating a serine to arginine mutation at aa 230. The cells were then harvested, and the levels of mRNA encoding ACE2 and SPP2 was evaluated by RT-qPCR. (C and D) Calu-3 cells were transfected with pcDNA (vector only) or the plasmid containing a CHI3L1 cDNA (pCHI3L1). They were simultaneously treated with flavopiridol (Flavo; 5 nM) (C) or BMS 265246 (BMS; 9 nM) (D) or their vehicle controls (5% DMSO) for 24 hours. The cells were then harvested, and the levels of mRNA encoding ACE2 and SPP were evaluated by RT-qPCR. A is representative immunoblots in 3 separate experiments. GAPDH was used as an internal control, The values in B and D are mean ± SEM. Each value in C is from a different animal, and the mean ± SEM is illustrated. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (1-way ANOVA with post hoc Tukey multiple comparison test).