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

Effects of a monoclonal antibody and small molecule inhibitor on CHI3L1 stimulation of ACE2 and SPP in vitro and in vivo.

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Effects of a monoclonal antibody and small molecule inhibitor on CHI3L1 ...
(A and B) Calu-3 cells were stimulated with vehicle (PBS) or rCHI3L1 (250 ng/mL) and treated with isotype control IgG or anti-CHI3L1 (FRG) for 48 hours. The cells were then harvested, and the levels of mRNA encoding ACE2 and SPP, and ACE2 and SPP protein, were evaluated by RT-qPCR (A) and immunoblot assays (B). (C) WT and CHI3L1 Tg mice were treated with IgG isotype control antibody or FRG antibody during their 2 weeks of transgene activation (i.p. every other day, 200 μg/mouse). The levels of mRNA encoding Ace2 and SPP were then evaluated using RT-qPCR. (D) Calu-3 cells were stimulated with vehicle (PBS) or rCHI3L1 (250 ng/mL) and treated with kasugamycin (250 ng/mL) or vehicle control (PBS) for 48 hours. The cells were then harvested, and the levels of mRNA encoding ACE2 and SPP were evaluated by RT-qPCR. (E) WT and CHI3L1 Tg mice were treated with vehicle (PBS) or kasugamycin (50 mg/kg/mouse, i.p. every other day) during their 2 weeks of transgene activation. The levels of mRNA encoding Ace2 and SPP were then evaluated using RT-qPCR. β-Actin or GAPDH was used as an internal control. Each value in A, C, and E is from a different animal, and the mean ± SEM is illustrated. B is representative of 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (1-way ANOVA with post hoc Tukey multiple comparison test).