Kamle Suchitra, Ma Bing, He Chuan Hua, Akosman Bedia, Zhou Yang, Lee Chang-Min, El-Deiry Wafik S, Huntington Kelsey, Liang Olin, Machan Jason T, Kang Min-Jong, Shin Hyeon Jun, Mizoguchi Emiko, Lee Chun Geun, Elias Jack A
bioRxiv. 2021 Feb 16:2021.01.05.425478. doi: 10.1101/2021.01.05.425478.
COVID-19 is caused by the SARS-CoV-2 (SC2) virus and is more prevalent and severe in the 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 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 demonstrated 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 coopts 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.
新型冠状病毒肺炎（COVID-19）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2，简称SC2）病毒引起，在老年人和患有合并症（CM）的患者中更为普遍且病情更严重。由于几丁质酶3样蛋白1（CHI3L1）在衰老和合并症过程中被诱导产生，因此对CHI3L1与SC2之间的关系进行了研究。在此，我们证明CHI3L1是SC2受体血管紧张素转换酶2（ACE2）和病毒刺突蛋白启动蛋白酶（SPP）的有效刺激物，ACE2和SPP在衰老过程中被诱导产生，并且抗CHI3L1、春雷霉素和磷酸化抑制剂可消除这些ACE2和SPP的诱导事件。人体研究还表明，老年人和患有合并症的患者循环中CHI3L1的水平升高，且与COVID-19的严重程度相关。这些研究表明，CHI3L1是ACE2和SPP的有效刺激物；这种诱导是导致SC2感染期间衰老效应的主要机制，并且CHI3L1利用CHI3L1轴增强SC2感染。CHI3L1在COVID-19的发病机制中起关键作用，是一个有吸引力的治疗靶点。
