Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virusmediated inflammation

被引:5
作者
Leborgne, Nathan G. F. [1 ,2 ]
Devisme, Christelle [1 ,2 ]
Kozarac, Nedim [1 ,2 ,3 ]
Veiga, Ines Berenguer [1 ,2 ]
Ebert, Nadine [1 ,2 ]
Godel, Aurelie [1 ,2 ]
Grau-Roma, Llorenc [4 ]
Scherer, Melanie [3 ,5 ]
Plattet, Philippe [5 ,6 ]
Thiel, Volker [1 ,2 ,6 ]
Zimmer, Gert [1 ,2 ]
Taddeo, Adriano [1 ,2 ]
Benarafa, Charaf [1 ,2 ,6 ,7 ]
机构
[1] Inst Virol & Immunol, Mittelhausern, Switzerland
[2] Univ Bern, Vetsuisse Fac, Dept Infect Dis & Pathobiol, Bern, Switzerland
[3] Univ Bern, Grad Sch Cellular & Biomed Sci, Bern, Switzerland
[4] Univ Bern, Inst Anim Pathol, Vetsuisse Fac, COMPATH, Bern, Switzerland
[5] Univ Bern, Vetsuisse Fac, Div Neurol Sci, Bern, Switzerland
[6] Univ Bern, Multidisciplinary Ctr Infect Dis MCID, Bern, Switzerland
[7] Inst Virol & Immunol, Sensemattstr 293, CH-3147 Mittelhausern, Switzerland
基金
瑞士国家科学基金会;
关键词
CATHEPSIN-G; SERINE-PROTEASE; ELASTASE; CLEAVAGE; ALPHA-1-ANTITRYPSIN; INHIBITION; REGULATORS; IMMUNITY; TMPRSS2; IL-33;
D O I
10.1172/jci.insight.174133
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Studies on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have highlighted the crucial role of host proteases for viral replication and the immune response. The serine proteases furin and TMPRSS2 and lysosomal cysteine proteases facilitate viral entry by limited proteolytic processing of the spike (S) protein. While neutrophils are recruited to the lungs during COVID-19 pneumonia, little is known about the role of the neutrophil serine proteases (NSPs) cathepsin G (CatG), elastase (NE), and proteinase 3 (PR3) on SARS-CoV-2 entry and replication. Furthermore, the current paradigm is that NSPs may contribute to the pathogenesis of severe COVID-19. Here, we show that these proteases cleaved the S protein at multiple sites and abrogated viral entry and replication in vitro. In mouse models, CatG significantly inhibited viral replication in the lung. Importantly, lung inflammation and pathology were increased in mice deficient in NE and/ or CatG. These results reveal that NSPs contribute to innate defenses against SARS-CoV-2 infection via proteolytic inactivation of the S protein and that NE and CatG limit lung inflammation in vivo. We conclude that therapeutic interventions aiming to reduce the activity of NSPs may interfere with viral clearance and inflammation in COVID-19 patients.
引用
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页数:13
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