Molecular Microbiology and Immunology.
Pathology and Laboratory Medicine.
JCI Insight. 2021 Nov 8;6(21):e148749. doi: 10.1172/jci.insight.148749.
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.
COVID-19 是由 SARS-CoV-2（SC2）引起的，在老年人和合并症（CM）患者中更为普遍和严重。由于几丁质酶 3 样蛋白 1（CHI3L1）在衰老和 CM 期间被诱导，因此研究了 CHI3L1 与 SC2 之间的关系。在这里，我们证明 CHI3L1 是 SC2 受体血管紧张素转换酶 2（ACE2）和病毒刺突蛋白前体蛋白酶（SPP）的有效刺激物，ACE2 和 SPP 在衰老过程中被诱导，而抗 CHI3L1、井冈霉素和磷酸化抑制剂可消除这些 ACE2 和 SPP 诱导事件。人类研究还表明，循环 CHI3L1 的水平在老年人和合并症患者中增加，并且与 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 SC2 感染期间衰老影响的主要机制，并且 CHI3L1 利用 CHI3L1 轴来增强 SC2 感染。CHI3L1 在 COVID-19 的发病机制中起着关键作用，是一种有吸引力的治疗靶点。
