Fibrinolysis influences SARS-CoV-2 infection in ciliated cells

Hou, Yapeng; Ding, Yan; Nie, Hongguang; Ji, Hong‐Long

doi:10.1101/2021.01.07.425801

Cited by 8 publications

(4 citation statements)

References 47 publications

(48 reference statements)

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“…Co-expression and upregulation of PLAU, TMPRSS2, and ACE2 was observed in airway epithelial cells from severe/moderate patients and SARS-CoV-2 infected cell lines. This, together with a plasmin-mediated cleavage, could make cells more susceptible to infection (93). Interestingly, we also observed an enhanced expression of PLAU in nasal epithelium from severe cases when compared to mild and controls, highlighting the crosslink between both tissues.…”

Section: Discussionsupporting

confidence: 51%

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

Gómez-Carballa

Rivero‐Calle

Pardo-Seco

et al. 2021

Preprint

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BackgroundCOVID-19 symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences.Methods and findingsWe carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. We then used a differential expression approach and pathways analysis to detect tissue specific immune severity signals in COVID-19 patients.Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were shown in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis.ConclusionsWe found severity-related signatures in patient tissues mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

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Section: Discussionsupporting

confidence: 51%

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

Gómez-Carballa

Rivero‐Calle

Pardo-Seco

et al. 2021

Preprint

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“…First of all, the increased transmissibility of Covid-19 is caused also by an inserted furin site in SARS-CoV-2 spike (S) protein, that is cleaved during virus entry. Recent data show that plasmin is able to cleave the S protein furin site, thus favoring SARS-CoV-2 infection ( Hou et al, 2021 ). Second, the Covid-19 patients often suffer from a prothrombotic state associated to severe coagulopathies, that is not fully investigated.…”

Section: Bacterial and Viral Infectionsmentioning

confidence: 99%

Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View

Alfano

Franco

Stoppelli

2022

Front. Cell Dev. Biol.

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Urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein. The uPAR primary ligand is the serine protease urokinase (uPA), converting plasminogen into plasmin, a broad spectrum protease, active on most extracellular matrix components. Besides uPA, the uPAR binds specifically also to the matrix protein vitronectin and, therefore, is regarded also as an adhesion receptor. Complex formation of the uPAR with diverse transmembrane proteins, including integrins, formyl peptide receptors, G protein-coupled receptors and epidermal growth factor receptor results in intracellular signalling. Thus, the uPAR is a multifunctional receptor coordinating surface-associated pericellular proteolysis and signal transduction, thereby affecting physiological and pathological mechanisms. The uPAR-initiated signalling leads to remarkable cellular effects, that include increased cell migration, adhesion, survival, proliferation and invasion. Although this is beyond the scope of this review, the uPA/uPAR system is of great interest to cancer research, as it is associated to aggressive cancers and poor patient survival. Increasing evidence links the uPA/uPAR axis to epithelial to mesenchymal transition, a highly dynamic process, by which epithelial cells can convert into a mesenchymal phenotype. Furthermore, many reports indicate that the uPAR is involved in the maintenance of the stem-like phenotype and in the differentiation process of different cell types. Moreover, the levels of anchor-less, soluble form of uPAR, respond to a variety of inflammatory stimuli, including tumorigenesis and viral infections. Finally, the role of uPAR in virus infection has received increasing attention, in view of the Covid-19 pandemics and new information is becoming available. In this review, we provide a mechanistic perspective, via the detailed examination of consolidated and recent studies on the cellular responses to the multiple uPAR activities.

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“…Another analysis of bulk BALF transcriptomes also demonstrated PLAUR downregulation in COVID-19 patients [ 51 ]. A more in-depth single-cell transcriptomic study of BALF by Hou et al, however, revealed that PLAU expression is strongly upregulated in severe COVID-19 cases as compared to healthy controls [ 53 ]. To resolve these controversies, here, we compared single-cell transcriptomic data obtained from warm postmortem lung biopsies of patients diseased from COVID-19-associated pneumonia and lung biopsies from individuals with pulmonary fibrosis and control samples from healthy donors [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19

Шмакова

Попов

Romanov

et al. 2023

IJMS

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Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in Plau-/- and Plaur-/-mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in Plaur-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial–mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in Plaur-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation.

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Fibrinolysis influences SARS-CoV-2 infection in ciliated cells

Cited by 8 publications

References 47 publications

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity

Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View

Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19

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