Neutrophil elastase decreases SARS-CoV-2 spike protein binding to human bronchial epithelia by clipping ACE-2 ectodomain from the epithelial surface

Kummarapurugu, Apparao B.; Hawkridge, Adam M.; Ma, Jonathan; Osei, Suzette Y.; Martin, Rebecca; Zheng, Shuo; Voynow, Judith A.

doi:10.1016/j.jbc.2023.104820

Cited by 3 publications

(4 citation statements)

References 51 publications

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“…This suggests that the main proteases of neutrophils that proteolytically degrade the S protein of SARS-CoV-2 are these 3 serine proteases. A recent study showed that NE cleaved the N-terminal ectodomain of recombinant ACE2, which interfered with the binding of recombinant trimeric S to ACE2 in vitro ( 42 ). The effect of CatG and PR3 on ACE2 was not reported.…”

Section: Discussionmentioning

confidence: 99%

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

Leborgne,

Devisme,

Kozarac

et al. 2024

JCI Insight

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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.

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Section: Discussionmentioning

confidence: 99%

“…The effect of CatG and PR3 on ACE2 was not reported. Cleavage of ACE2 by NE suggests an additional antiviral mechanism for NE, although this was not directly investigated ( 42 ). Our in vitro data suggest that the blockade of VSV*ΔG-S Δ21 entry is principally mediated by the proteolytic degradation of S by the 3 NSPs.…”

Section: Discussionmentioning

confidence: 99%

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

Leborgne,

Devisme,

Kozarac

et al. 2024

JCI Insight

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“…The use of elastase as an activating protease has been reported for SARS-CoV-1, which may play a factor in promoting the initial inflammatory response to infection, but the situation for SARS-CoV-2 is less clear [ 36 ]. As with any virus-activating protease, the enzyme exists in tissue as part of a tightly regulated system, with neutrophil elastase proposed to be involved in ACE2 shedding, and so it has a protective effect for COVID [ 84 ]. Interestingly, engineering influenza HA to be elastase-cleaved has been used as a means to generate a live-attenuated vaccine virus [ 85 ].…”

Section: Serine Proteasesmentioning

confidence: 99%

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

Lubinski,

Whittaker

2024

Viruses

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Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

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“…CM was used to expose primary human bronchial epithelial (HBE) cells to NE or a control vehicle. NE-treated HBE cells exhibited decreased spike protein binding to HBE and the release of ACE-2 ectodomain fragments, resulting in decreased susceptibility to SARS-CoV-2 infection [ 149 ].…”

Section: The Role Of Cms In Cell-free Therapy Of Covid-19mentioning

confidence: 99%

The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm—A Powerful Therapeutic Tool for COVID-19 Patients

et al. 2023

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Currently, there is still no effective and definitive cure for the coronavirus disease 2019 (COVID-19) caused by the infection of the novel highly contagious severe acute respiratory syndrome virus (SARS-CoV-2), whose sudden outbreak was recorded for the first time in China in late December 2019. Soon after, COVID-19 affected not only the vast majority of China’s population but the whole world and caused a global health public crisis as a new pandemic. It is well known that viral infection can cause acute respiratory distress syndrome (ARDS) and, in severe cases, can even be lethal. Behind the inflammatory process lies the so-called cytokine storm (CS), which activates various inflammatory cytokines that damage numerous organ tissues. Since the first outbreak of SARS-CoV-2, various research groups have been intensively trying to investigate the best treatment options; however, only limited outcomes have been achieved. One of the most promising strategies represents using either stem cells, such as mesenchymal stem cells (MSCs)/induced pluripotent stem cells (iPSCs), or, more recently, using cell-free approaches involving conditioned media (CMs) and their content, such as extracellular vesicles (EVs) (e.g., exosomes or miRNAs) derived from stem cells. As key mediators of intracellular communication, exosomes carry a cocktail of different molecules with anti-inflammatory effects and immunomodulatory capacity. Our comprehensive review outlines the complex inflammatory process responsible for the CS, summarizes the present results of cell-free-based pre-clinical and clinical studies for COVID-19 treatment, and discusses their future perspectives for therapeutic applications.

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Neutrophil elastase decreases SARS-CoV-2 spike protein binding to human bronchial epithelia by clipping ACE-2 ectodomain from the epithelial surface

Cited by 3 publications

References 51 publications

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

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

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm—A Powerful Therapeutic Tool for COVID-19 Patients

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