IL11 involvement in inflammatory and pro-fibrotic alterations via STAT3-WNT5A signaling activation by SARS-CoV-2 accessory proteins
| Autor: | Dies López-Ayllón, Blanca, García-García, Tránsito, Mendoza, Laura, Lucas-Rius, Ana de, Fernández-Rodríguez, Raúl, Redondo, Natalia, Pedrucci, Federica, Zaldívar-López, Sara, Jiménez-Marín, Ángeles, Garrido, Juan J., Montoya, María |
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| Přispěvatelé: | European Commission, Consejo Superior de Investigaciones Científicas (España), Junta de Andalucía, Ministerio de Ciencia e Innovación (España), Dies López-Ayllón, Blanca, García-García, Tránsito, Mendoza, Laura, Lucas-Rius, Ana de, Fernández-Rodríguez, Raúl, Redondo, Natalia, Zaldívar-López, Sara, Jiménez-Marín, Ángeles, Garrido, Juan J., Montoya, María |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Popis: | 1 p.-6 fig. SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood and several of them have been mutating into the different variants of the virus. WNT5A dysregulation signaling has been implicated in the development of various pathological conditions in humans such as inflammation and fibrosis. Interleukin-6 (IL6) family members induce WNT5A expression in various cell types, highlighting a critical role for WNT5A in immune responses. Expression of Interleukin-11 (IL11), a member of IL6 cytokine family, correlates with the extent of fibrosis and its signaling induced fibroblast activation via TGFβ. In this study, A549 were transduced with lentivirus expressing individual viral accessory proteins ORF6, ORF8,ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate) and their interaction with cellular responses were analyzed. Firstly, transcriptomic analysis revealed that both WNT5A and IL11 were significantly up-regulated in all transduced cells. Some IL11 signaling-related genes, such as STAT3 or TGFβ, were differentially expressed. IPA software analysis showed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease. Subsequently, bioinformatics and functional assays revealed that these four accessory proteins were implicated in both inflammatory and fibrotic responses. While overexpression of ORF8 and ORF9c appear to trigger a STAT3-dependent cellular response mediated by IL11, ORF6 and ORF9b seem to provoke a cell profibrotic response mediated by TGFb through WNT5A. Our results suggest that ORF6, ORF8, ORF9b and ORF9c could be involved in inflammatory and fibrotic responses in SARS-CoV-2 infection. Thus, these accessory proteins could be targeted by new therapies for COVID-19 disease. This research work was funded by the European Commission – NextGenerationEU(Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI+ Salud Global), Junta de Andalucía (CV20-20089) and Spanish Ministry of Science project PID2021-123399OB-I00. |
| Databáze: | OpenAIRE |
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