炎症
生物
蛋白酶
复制(统计)
激肽释放酶
寄主(生物学)
蛋白酶抑制剂(药理学)
免疫学
病毒学
人类免疫缺陷病毒(HIV)
遗传学
酶
生物化学
抗逆转录病毒疗法
病毒载量
作者
Hyunjoon Kim,Yeong-Lim Kang,Se‐Mi Kim,Dong Bin Park,Sungeun Heo,Ji‐Seung Yoo,I. W. Choi,Monford Paul Abishek N,Jae-Woo Ahn,Jeong‐Sun Yang,Nayeon Bak,Kyeong Kyu Kim,Joo-Yeon Lee,Young Ki Choi
出处
期刊:PubMed
日期:2024-08-20
卷期号:17 (850): eadn3785-eadn3785
标识
DOI:10.1126/scisignal.adn3785
摘要
Coronaviruses rely on host proteases to activate the viral spike protein, which facilitates fusion with the host cell membrane and the release of viral genomic RNAs into the host cell cytoplasm. The distribution of specific host proteases in the host determines the host, tissue, and cellular tropism of these viruses. Here, we identified the kallikrein (KLK) family member KLK5 as a major host protease secreted by human airway cells and exploited by multiple human betacoronaviruses. KLK5 cleaved both the priming (S1/S2) and activation (S2') sites of spike proteins from various human betacoronaviruses in vitro. In contrast, KLK12 and KLK13 displayed preferences for either the S2' or S1/S2 site, respectively. Whereas KLK12 and KLK13 worked in concert to activate SARS-CoV-2 and MERS-CoV spike proteins, KLK5 by itself efficiently activated spike proteins from several human betacoronaviruses, including SARS-CoV-2. Infection of differentiated human bronchial epithelial cells (HBECs) with human betacoronaviruses induced an increase in KLK5 that promoted virus replication. Furthermore, ursolic acid and other related plant-derived triterpenoids that inhibit KLK5 effectively suppressed the replication of SARS-CoV, MERS-CoV, and SARS-CoV-2 in HBECs and mitigated lung inflammation in mice infected with MERS-CoV or SARS-CoV-2. We propose that KLK5 is a pancoronavirus host factor and a promising therapeutic target for current and future coronavirus-induced diseases.
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