SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells
SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain u...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Microorganisms |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-2607/9/7/1438 |
| id |
doaj-a6bd25dff9ef4d079ce1bc8293cff614 |
|---|---|
| record_format |
Article |
| spelling |
doaj-a6bd25dff9ef4d079ce1bc8293cff6142021-07-23T13:55:13ZengMDPI AGMicroorganisms2076-26072021-07-0191438143810.3390/microorganisms9071438SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial CellsFrancesca Caccuri0Antonella Bugatti1Alberto Zani2Antonella De Palma3Dario Di Silvestre4Ekta Manocha5Federica Filippini6Serena Messali7Paola Chiodelli8Giovanni Campisi9Simona Fiorentini10Fabio Facchetti11Pierluigi Mauri12Arnaldo Caruso13Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalyProteomic and Metabolomic Laboratory, Institute of Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, ItalyProteomic and Metabolomic Laboratory, Institute of Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of General Pathology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalyPathology Unit, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalyProteomic and Metabolomic Laboratory, Institute of Biomedical Technologies, National Research Council (ITB-CNR), 20054 Segrate, ItalySection of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, ItalySARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of pro-inflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection.https://www.mdpi.com/2076-2607/9/7/1438COVID-19endothelial cell dysfunctioninfectionangiogenesisproteome |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Francesca Caccuri Antonella Bugatti Alberto Zani Antonella De Palma Dario Di Silvestre Ekta Manocha Federica Filippini Serena Messali Paola Chiodelli Giovanni Campisi Simona Fiorentini Fabio Facchetti Pierluigi Mauri Arnaldo Caruso |
| spellingShingle |
Francesca Caccuri Antonella Bugatti Alberto Zani Antonella De Palma Dario Di Silvestre Ekta Manocha Federica Filippini Serena Messali Paola Chiodelli Giovanni Campisi Simona Fiorentini Fabio Facchetti Pierluigi Mauri Arnaldo Caruso SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells Microorganisms COVID-19 endothelial cell dysfunction infection angiogenesis proteome |
| author_facet |
Francesca Caccuri Antonella Bugatti Alberto Zani Antonella De Palma Dario Di Silvestre Ekta Manocha Federica Filippini Serena Messali Paola Chiodelli Giovanni Campisi Simona Fiorentini Fabio Facchetti Pierluigi Mauri Arnaldo Caruso |
| author_sort |
Francesca Caccuri |
| title |
SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells |
| title_short |
SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells |
| title_full |
SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells |
| title_fullStr |
SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells |
| title_full_unstemmed |
SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells |
| title_sort |
sars-cov-2 infection remodels the phenotype and promotes angiogenesis of primary human lung endothelial cells |
| publisher |
MDPI AG |
| series |
Microorganisms |
| issn |
2076-2607 |
| publishDate |
2021-07-01 |
| description |
SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of pro-inflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection. |
| topic |
COVID-19 endothelial cell dysfunction infection angiogenesis proteome |
| url |
https://www.mdpi.com/2076-2607/9/7/1438 |
| work_keys_str_mv |
AT francescacaccuri sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT antonellabugatti sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT albertozani sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT antonelladepalma sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT dariodisilvestre sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT ektamanocha sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT federicafilippini sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT serenamessali sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT paolachiodelli sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT giovannicampisi sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT simonafiorentini sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT fabiofacchetti sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT pierluigimauri sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells AT arnaldocaruso sarscov2infectionremodelsthephenotypeandpromotesangiogenesisofprimaryhumanlungendothelialcells |
| _version_ |
1721287025508745216 |