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The host protease KLK5 primes and activates spike proteins to promote human betacoronavirus replication and lung inflammation

Hyunjoon Kim,Yeonglim Kang,Semi Kim,Dongbin Park,Seo-Young Heo,Ji-Seung Yoo,Isaac Choi,Monford Paul Abishek N,Jae-Woo Ahn,Jeong-Sun Yang,Nayeon Bak,K. Kim,Joo-Yeon Lee,Y. Choi

Published 2024 in Science Signaling

ABSTRACT

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. SARS-CoV-2 and other coronaviruses use host protease KLK5 to process spike proteins needed for infection. Editor’s summary For a coronavirus to enter and infect cells, its spike protein must be sequentially processed at priming and activating sites by host proteases. Kim et al. found that the secreted protease KLK5 cleaved both sites in betacoronavirus spike proteins. KLK5 abundance increased in human airway cells infected with betacoronaviruses, and knockdown or inhibition of KLK5 reduced betacoronavirus replication in cells. KLK5 inhibitors also reduced lung inflammation in mice infected with SARS-CoV-2 or MERS-CoV, suggesting that they could be used to treat diseases caused by known and emerging coronaviruses. —Annalisa M. VanHook

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