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 1

CHI3L1 stimulates pulmonary ACE2 and SPP.

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CHI3L1 stimulates pulmonary ACE2 and SPP. Eight-week-old WT (–) and CHI3...
Eight-week-old WT (–) and CHI3L1 Tg (+) mice were sacrificed after 2 weeks of transgene induction with doxycycline. Levels of Ace2 and SPP mRNA and protein in lungs from WT and CHI3L1 Tg mice were evaluated using lung lysates and paraffin tissue blocks. (A) Comparisons of expression levels of ACE2 and SPP in lungs from WT (Tg–) and CHI3L1 Tg+ mice using semiquantitative real-time reverse transcription PCR (RT-qPCR) indexed to β-actin controls. (B) Western immunoblot comparisons of ACE2 and SPP levels in lungs from WT (Tg–) and CHI3L1 Tg+ mice. (C and D) IHC of ACE2, CTSL, and TMPRSS2 in lungs from WT and CHI3L1 Tg mice. (E) Double-label IHC comparing localization of ACE2, TMPRSS2, and CD31 in lungs from CHI3L1 Tg mice. Arrows on C–E indicate stain+ cells. Each value in A is from a different animal; mean ± SEM is illustrated. B–E are representative of at least 3 separate evaluations. β-Actin was used as an internal control. ACE2, murine angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2; CTSL, Cathepsin L. Scale bars: 100 μm. *P < 0.05 (Student t test).