Serine Protease Inhibitors Restrict Host Susceptibility to SARS-CoV-2 Infections

Rosendal, Ebba; Mihai, Ionut Sebastian; Becker, Miriam; Das, Debojyoti; Frängsmyr, Lars; Persson, B. David; Rankin, Gregory; Gröning, Remigius; Trygg, Johan; Forsell, Mattias N.E.; Ankarklev, Johan; Blomberg, Anders; Henriksson, Johan; Överby, Anna K.; Lenman, Annasara

doi:10.1128/mbio.00892-22

Cited by 22 publications

(31 citation statements)

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“…This model was used to characterize the cellular pathways affected by SARS-CoV-2 infection and the effects of corticosteroid treatment with respect to inflammation and HA metabolism. The cells were differentiated at an air-liquid interface (ALI) to form a polarized epithelium containing an apical layer of fully functional secretory and ciliated cells and an underlying layer of basal cells (18). The lung cultures were treated with, or without, the corticosteroid betamethasone, and infected with SARS-CoV-2 (figure 4A).…”

Section: Resultsmentioning

confidence: 99%

“…Primary human bronchial epithelial cells (HBEC) were isolated from proximal airway tissue obtained with informed consent from two patients, who underwent thoracic surgery at the University Hospital, Umeå, Sweden (ethical permission approved by the Regional Swedish Ethical Review Authority in Umeå). HBECs were grown and differentiated at an air-liquid interface (ALI) forming an in vitro 3D-lung model as previously described (16). In short, HBECs were grown and differentiated on 6.5 mm semipermeable transwell inserts (0.4 µm Pore Polyester Membrane Insert, Corning) and after two weeks at air-liquid interface (ALI) the cultures reached full differentiation, which was assessed using light microscopy focusing on epithelial morphology, presence of ciliated cells, and mucus production along with immunofluorescence staining for ciliated cells (acetylated-tubulin, T6793, Sigma) and goblet cells (muc5AC, Ab-1 (45M1), #MS-145-P, ThermoFisher).…”

Section: D-lung Model (I) Generation Of the Human Primary 3d-lung Modelmentioning

confidence: 99%

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Hyaluronan in COVID-19 morbidity, a bedside-to-bench approach to understand mechanisms and long-term consequences of hyaluronan

Hellman

Rosendal

Edin

et al. 2023

Preprint

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Rationale: High levels of hyaluronan in lungs and blood associate with COVID-19 severity. However, the effects on systemic hyaluronan concentrations and the mechanisms involved in the pathological overproduction of hyaluronan upon SARS-CoV-2 infection remain incompletely characterized. Objectives: To determine how hyaluronan levels in blood of COVID-19 patients change over time and investigate SARS-CoV-2 impact on hyaluronan metabolism along with the effect of corticosteroid treatment. Methods: The concentrations of hyaluronan were measured in blood plasma from patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS 6-9), both during the acute and convalescent phases. Primary human bronchial epithelial cells isolated from healthy donors were differentiated into an in vitro 3D-lung model and used to study effects of SARS-CoV-2 infection and corticosteroids treatment on hyaluronan metabolism. Measurements and Main results: Compared to healthy controls, both patients with mild and severe COVID-19 showed elevated plasma hyaluronan concentrations, which increased with disease severity. A reduction was observed over time, but hyaluronan levels remained elevated for at least 12 weeks, especially in women. SARS-CoV-2 infection in the 3D-lung model showed upregulation of inflammatory genes, hyaluronan synthases and downregulation of hyaluronidases, which increased the overall hyaluronan concentration. Notably, several of these effects were counteracted by corticosteroid treatment. Conclusions: Overproduction of hyaluronan plays a role in the pathogenesis of COVID-19 and hyaluronan levels in blood remain elevated over time. The in vitro mechanism for the positive effects of corticosteroid treatment in COVID-19 suggests a combined action of reduced inflammation and counteraction of hyaluronan synthesis.

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Section: Resultsmentioning

confidence: 99%

Section: D-lung Model (I) Generation Of the Human Primary 3d-lung Modelmentioning

confidence: 99%

Hyaluronan in COVID-19 morbidity, a bedside-to-bench approach to understand mechanisms and long-term consequences of hyaluronan

Hellman

Rosendal

Edin

et al. 2023

Preprint

Self Cite

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“…There are many biological pathways through which a given effect can occur. To inhibit the harmful effects of spike protein, it is possible to target furin cleavage, either by directly binding to the furin cleavage site itself [85][86][87] or by interfering with the serine protease reaction [88][89][90] , to block the interaction by binding to ACE2 91 , downregulating ACE2 expression 92 , inhibiting the transition to the active conformation of S protein 93 , or binding the RBD of spike protein and allosterically inhibiting interaction with ACE2 94 (Figure 1). Clearing of spike proteins can also be accomplished by increasing autophagy, which clears proteins and recycles their amino acids 95 .…”

Section: Therapeuticsmentioning

confidence: 99%

Strategies for the Management of Spike Protein-Related Pathology

Halma¹,

Plothe²,

Lawrie³

2023

Preprint

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In the wake of the Covid-19 crisis, a need has arisen to prevent and treat two related conditions, Covid vaccine injury and long Covid, both of which have a significant vascular component. Therefore, the management of these conditions require the development of strategies to prevent or dissolve blood clots and restore circulatory health. This review summarizes the evidence on strategies that can be applied to treat both long and vaccine injuries based on similar mechanisms of action.

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“…They have reported a marked reduction in inflammatory biomarkers in BALF that are responsible for leukocyte activation, chemotaxis, and recruitment, reduction in NE and CG activity and elastolysis markers in BALF. Invitro transcriptomic data derived from 3D lung model, people who are less susceptible to COVID-19 express higher level of antiprotease genes including SERPINA-1 [112]. Growing evidence suggest that AAT can be a suitable candidate to treat COVID-19 due to its anti-viral and anti-inflammatory roles.…”

Section: Aat Protection Against Covid-19mentioning

confidence: 99%

COVID-19 Pathology Sheds New Light on Balance between Neutrophil Proteases and Their Inhibitors

Radic¹,

Silva²

2022

Preprint

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Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the con-comitant release of granule contents that damage surrounding tissues into sharp focus. Neutro-phil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. In-terestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promote lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and increase the risk of allergic responses. Recent observations point to the fact that re-duced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19

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Serine Protease Inhibitors Restrict Host Susceptibility to SARS-CoV-2 Infections

Cited by 22 publications

References 50 publications

Hyaluronan in COVID-19 morbidity, a bedside-to-bench approach to understand mechanisms and long-term consequences of hyaluronan

Hyaluronan in COVID-19 morbidity, a bedside-to-bench approach to understand mechanisms and long-term consequences of hyaluronan

Strategies for the Management of Spike Protein-Related Pathology

COVID-19 Pathology Sheds New Light on Balance between Neutrophil Proteases and Their Inhibitors

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