Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation
Nathan G.F. Leborgne, Christelle Devisme, Nedim Kozarac, Inês Berenguer Veiga, Nadine Ebert, Aurélie Godel, Llorenç Grau-Roma, Melanie Scherer, Philippe Plattet, Volker Thiel, Gert Zimmer, Adriano Taddeo, Charaf Benarafa
Nathan G.F. Leborgne, Christelle Devisme, Nedim Kozarac, Inês Berenguer Veiga, Nadine Ebert, Aurélie Godel, Llorenç Grau-Roma, Melanie Scherer, Philippe Plattet, Volker Thiel, Gert Zimmer, Adriano Taddeo, Charaf Benarafa
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Research Article COVID-19 Inflammation

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

Abstract

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.

Authors

Nathan G.F. Leborgne, Christelle Devisme, Nedim Kozarac, Inês Berenguer Veiga, Nadine Ebert, Aurélie Godel, Llorenç Grau-Roma, Melanie Scherer, Philippe Plattet, Volker Thiel, Gert Zimmer, Adriano Taddeo, Charaf Benarafa

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Figure 2

CatG–/– mice have increased viral replication in the lungs and in the nose compared with WT mice.

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CatG–/– mice have increased viral replication in the lungs and in the n...
WT, CatG–/–, NE–/–, PR3–/–, and NE.CatG–/– mice were inoculated intranasally with 1 × 104 TCID50 SARS-CoV-2MA10. (A) Relative body weight change overtime after infection. Data were analyzed by 2-way ANOVA with Dunett’s multiple-comparison test, comparing the knockout groups to the WT group. Data were pooled from 6 independent experiments (n = 12–31 mice/group). *P < 0.05; color of asterisk corresponds to the genotype. (B) Viral copy numbers were determined by RT-qPCR in oropharyngeal swabs or tissue homogenates. (C) Viral titers in lung homogenates. (B and C) Data were log10 transformed and analyzed by 1-way ANOVA with Dunnett’s multiple-comparison test comparing the knockout groups to the WT group at each time point. Data pooled from 7 independent experiments (2 dpi, n = 16–19/group; 4 dpi, n = 10–17/group). *P < 0.05, **P < 0.01, ***P < 0.001.