Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling
Abstract
:1. Introduction
2. Methods
2.1. Cell Culture
2.2. SARS-CoV-2 Isolate
2.3. SARS-CoV-2 Challenge
2.4. Viral Quantification
2.5. RNA Libraries and Sequencing (RNA-Seq)
2.6. RNA-Seq Data Analysis
2.7. Downstream RNA-Seq Analysis
2.8. RT-qPCR
2.9. Western Blotting
2.10. Immunofluorescence
2.11. Quantitative Analysis of Mitochondrial Network Morphology
2.12. Angiogenesis-Related Protein Secretome
2.13. Transmission Electron Microscopy
2.14. Statistical Analyses
3. Results
3.1. Characterization of HBMEC Challenge by SARS-CoV-2
3.2. SARS-CoV-2 Affects Tight Junction Genes Expression in BBB-Forming Cells
3.3. Exposure to SARS-CoV-2 Promotes Endothelial Activation and Hyper-Inflammatory Response In Vitro
3.4. Angiogenic Profiling of SARS-CoV-2-Exposed HBMEC Cells
3.5. Mitochondrial Plasticity Is Affected by Exposure to SARS-CoV-2
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Gene Name | Symbol | Fold-Change (Log) | p Value | FDR |
---|---|---|---|---|
Uncategorized gene | RP11-298I3.3 | −2.19 | 0.00001795234598 | 0.04214061886 |
ankyrin repeat domain 36C | ANKRD36C | −1.42 | 0.000000005528613831 | 0.00002495701339 |
upstream transcription factor family member 3 | USF3 | −0.76 | 0.00002036226065 | 0.04595918861 |
SMG1 nonsense mediated mRNA decay associated PI3K related kinase | SMG1 | −0.75 | 0.000002651386726 | 0.007779698933 |
nuclear factor kappa B subunit 2 | NFKB2 | 0.64 | 0.00002117775188 | 0.04602945153 |
E74 like ETS transcription factor 3 | ELF3 | 0.82 | 0.00001027948854 | 0.02601045479 |
ephrin A1 | EFNA1 | 0.82 | 0.0000001766175517 | 0.0006096837885 |
Epstein–Barr-virus-induced 3 | EBI3 | 0.87 | 0.000005771957935 | 0.01612959902 |
intercellular adhesion molecule 1 | ICAM1 | 0.97 | 0 | 0.0000005593411357 |
complement C3 | C3 | 1.01 | 0.000000004506547278 | 0.00002203851837 |
NFKB inhibitor alpha | NFKBIA | 1.05 | 0 | 0.00000008288304584 |
C-C motif chemokine ligand 2 | CCL2 | 1.14 | 0.000000002315586268 | 0.00001235344223 |
baculoviral IAP repeat containing 3 | BIRC3 | 1.27 | 0.00000002052506134 | 0.00007528079373 |
zinc finger CCCH-type containing 12A | ZC3H12A | 1.29 | 0 | 0.0000003145723235 |
RELB proto-oncogene, NF-kB subunit | RELB | 1.30 | 0 | 0.00000008288304584 |
Uncharacterized protein | AC010646.3 | 1.31 | 0.0000103901062 | 0.02601045479 |
interleukin 6 | IL6 | 1.36 | 0 | 0.00000002581261588 |
TNF alpha induced protein 3 | TNFAIP3 | 1.38 | 0.00000001761165902 | 0.00006890150651 |
TNF alpha induced protein 2 | TNFAIP2 | 1.42 | 0.000001921435199 | 0.005934605433 |
C-X-C motif chemokine ligand 2 | CXCL2 | 1.79 | 0 | 0 |
TNF superfamily member 18 | TNFSF18 | 1.95 | 0.0000106374977 | 0.02601045479 |
C-X-C motif chemokine ligand 1 | CXCL1 | 2.24 | 0 | 0 |
C-X-C motif chemokine ligand 3 | CXCL3 | 2.32 | 0.0000000001312489102 | 0.0000007702211048 |
C-C motif chemokine ligand 20 | CCL20 | 3.50 | 0.000000007991169552 | 0.00003349669957 |
pentraxin 3 | PTX3 | 4.30 | 0 | 0 |
lymphotoxin beta | LTB | 5.04 | 0 | 0 |
Analyte Name (Alternate Nomenclature) | Gene ID | Foreground Pixel Intensity (Fold Change Relative to Mock) | ||
---|---|---|---|---|
Mock | MOI 0.01 | MOI 0.1 | ||
Activin-A | 3624 | 55.5 | 32.5 (0.6) | 88.5 (1.63) |
ADAMTS-1 | 9510 | 25.5 | 12.5 (0.52) | 45.5 (1.88) |
Angiogenin (ANG) | 283 | 6427 | 7818 (1.21) | 6553 (1.01) |
Angiopoietin-1 (Ang-1) | 284 | 147 | 86 (0.59) | 155 (1.07) |
Angiopoietin-2 (Ang-2) | 285 | 39.5 | 12 (0.32) | 79.5 (2.08) |
Angiostatin/ Plasminigen | 5340 | 144.5 | 10 (0.07) | 74 (0.52) |
Amphiregulin (AR) | 374 | 5797 | 6744 (1.16) | 5064.5 (0.87) |
Artemin | 9048 | 144.5 | 143 (0.99) | 64 (0.46) |
Coagulation Factor III (TF) | 2152 | 818 | 887 (1.08) | 622 (0.76) |
CXCL16 | 58,191 | 3387.5 | 3976.5 (1.17) | 2521.5 (0.74) |
DPPIV (CD26) | 1803 | 72.5 | 1.5 (0.03) | 203 (2.83) |
EGF | 1950 | 16.5 | 18 (1.15) | 40.5 (2.60) |
EG-VEGF (PK1) | 84,432 | 188.5 | 164 (0.88) | 257 (1.38) |
Endoglin (CD105) | 2022 | 17.5 | 17.5 (1.05) | 74.5 (4.40) |
Endostatin/ Collagen XVIII | 80,781 | 3827 | 4747.5 (1.24) | 3931.5 (1.02) |
Endothelin-1 (ET-1) | 1906 | 9087.5 | 9213 (1.01) | 9007.5 (0.99) |
FGF acidic (FGF-1) | 2246 | 475 | 69.5 (0.15) | 472.5 (1) |
FGF basic (FGF2) | 2247 | 16.5 | 5 (0.36) | 4.5 (0.42) |
FGF-4 | 2249 | 0.5 | −1 | 36.5 (78.0) |
FGF-7 (KGF) | 2252 | 77.5 | 15.5 (0.21) | 180 (2.34) |
GDNF | 2668 | 101 | 82 (0.82) | 105 (1.06) |
GM-CSF | 1437 | 419.5 | 275 (0.65) | 241.5 (0.58) |
HB-EGF | 1839 | 71 | 32.5 (0.47) | 134 (1.92) |
HGF | 3082 | 10.5 | 11 (1.14) | 25.5 (2.66) |
IGFBP-1 | 3484 | 4841.5 | 4901 (1.01) | 4684.5 (0.96) |
IGFBP-2 | 3485 | 118 | 22.5 (0.19) | 154.5 (1.33) |
IGFBP-3 | 3486 | 3203 | 5335.5 (1.66) | 3991 (1.24) |
IL-1β (IL-1F2) | 3553 | 512 | 470.5 (0.92) | 695.5 (1.36). |
IL-8 (CXCL8) | 3576 | 10,875.5 | 10,484.5 (0.96) | 10,744 (0.98) |
LAP (TGF B1) | 7040 | 292.5 | 219.5 (0.75) | 102 (0.35) |
Leptin | 3952 | 1 | 44 (45.0) | 43.5 (46.0) |
MCP-1 (CCL2) | 6347 | 4549 | 7624 (1.67) | 4759 (1.04) |
MIP-1A (CCL3) | 6348 | 123 | 103 (0.84) | 149 (1.23) |
MMP-8 | 4317 | 418 | 510.5 (1.22) | 841.5 (2.01) |
MMP-9 | 4318 | 298.5 | 106.5 (0.36) | 206 (0.69) |
NRG1-B1 (HRG1-β1) | 3084 | 256 | 107.5 (0.42) | 320 (1.25) |
Pentraxin-3 (TSG-14) | 5806 | 7509.5 | 7263.5 (0.96) | 8523 (1.13) |
PD-ECGF | 1890 | 441 | 310 (0.70) | 600 (1.36) |
PDGF-AA | 5154 | 1411.5 | 2129.5 (1.50) | 1736.5 (1.23) |
PDGF-AB/ PDGF-BB | 5155 | 923.5 | 878 (0.95) | 1161 (1.25) |
Persephin | 5623 | 565.5 | 375.5 (0.66) | 490.5 (0.87) |
Platelet Factor 4 (CXCL4) | 5196 | 261.5 | 150.5 (0.58) | 283.5 (1.09) |
PIGF | 5228 | 50.5 | 14 (0.29) | 90 (1.83) |
Prolactin | 5617 | 7 | 49 (7.14) | 57 (8.5) |
Serpin B5 (Maspin) | 5268 | 604 | 578 (0.95) | 694 (1.15) |
Serpin-E1 (PAI-1) | 5054 | 10,979.5 | 10,955.5 (0.99) | 11,590.5 (1.05) |
Serpin-F1 (PEDF) | 5176 | 422.5 | 327.5 (0.77) | 476 (1.13) |
TIMP-1 | 7076 | 9548 | 9156 (0.95) | 10,696 (1.12) |
TIMP-4 | 7079 | 446.5 | 292.5 (0.65) | 656.5 (1.47) |
Thrombospondin-1 (TSP-1) | 7057 | 9842 | 9012 (0.91) | 9727.5 (0.98) |
Thrombospondin-2 (TSP-2) | 7058 | 688 | 929 (1.35) | 837 (1.22) |
uPA | 5328 | 12,865 | 13,396.5 (1.04) | 14,065 (1.09) |
Vasohibin | 22,846 | 253 | 172 (0.68) | 268 (1.06) |
VEGF | 7422 | 9700.5 | 9954 (10.2) | 10,559.5 (1.08) |
VEGF-C | 7424 | 0.5 | 0 | 37 (79.0) |
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Motta, C.S.; Torices, S.; da Rosa, B.G.; Marcos, A.C.; Alvarez-Rosa, L.; Siqueira, M.; Moreno-Rodriguez, T.; Matos, A.d.R.; Caetano, B.C.; Martins, J.S.C.d.C.; et al. Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling. Viruses 2023, 15, 745. https://doi.org/10.3390/v15030745
Motta CS, Torices S, da Rosa BG, Marcos AC, Alvarez-Rosa L, Siqueira M, Moreno-Rodriguez T, Matos AdR, Caetano BC, Martins JSCdC, et al. Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling. Viruses. 2023; 15(3):745. https://doi.org/10.3390/v15030745
Chicago/Turabian StyleMotta, Carolline Soares, Silvia Torices, Barbara Gomes da Rosa, Anne Caroline Marcos, Liandra Alvarez-Rosa, Michele Siqueira, Thaidy Moreno-Rodriguez, Aline da Rocha Matos, Braulia Costa Caetano, Jessica Santa Cruz de Carvalho Martins, and et al. 2023. "Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling" Viruses 15, no. 3: 745. https://doi.org/10.3390/v15030745