AHR is a Zika virus host factor and a candidate target for antiviral therapy
Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV in...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/138398 |
| _version_ | 1811088319017123840 |
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| author | Giovannoni, Federico Bosch, Irene Polonio, Carolina Manganeli Torti, María F Wheeler, Michael A Li, Zhaorong Romorini, Leonardo Rodriguez Varela, María S Rothhammer, Veit Barroso, Andreia Tjon, Emily C Sanmarco, Liliana M Takenaka, Maisa C Modaresi, Seyed Mohamad Sadegh Gutiérrez-Vázquez, Cristina Zanluqui, Nágela Ghabdan dos Santos, Nilton Barreto Munhoz, Carolina Demarchi Wang, Zhongyan Damonte, Elsa B Sherr, David Gehrke, Lee Peron, Jean Pierre Schatzmann Garcia, Cybele C Quintana, Francisco J |
| author_facet | Giovannoni, Federico Bosch, Irene Polonio, Carolina Manganeli Torti, María F Wheeler, Michael A Li, Zhaorong Romorini, Leonardo Rodriguez Varela, María S Rothhammer, Veit Barroso, Andreia Tjon, Emily C Sanmarco, Liliana M Takenaka, Maisa C Modaresi, Seyed Mohamad Sadegh Gutiérrez-Vázquez, Cristina Zanluqui, Nágela Ghabdan dos Santos, Nilton Barreto Munhoz, Carolina Demarchi Wang, Zhongyan Damonte, Elsa B Sherr, David Gehrke, Lee Peron, Jean Pierre Schatzmann Garcia, Cybele C Quintana, Francisco J |
| author_sort | Giovannoni, Federico |
| collection | MIT |
| description | Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity. |
| first_indexed | 2024-09-23T14:00:20Z |
| format | Article |
| id | mit-1721.1/138398 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:00:20Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1383982021-12-09T03:15:05Z AHR is a Zika virus host factor and a candidate target for antiviral therapy Giovannoni, Federico Bosch, Irene Polonio, Carolina Manganeli Torti, María F Wheeler, Michael A Li, Zhaorong Romorini, Leonardo Rodriguez Varela, María S Rothhammer, Veit Barroso, Andreia Tjon, Emily C Sanmarco, Liliana M Takenaka, Maisa C Modaresi, Seyed Mohamad Sadegh Gutiérrez-Vázquez, Cristina Zanluqui, Nágela Ghabdan dos Santos, Nilton Barreto Munhoz, Carolina Demarchi Wang, Zhongyan Damonte, Elsa B Sherr, David Gehrke, Lee Peron, Jean Pierre Schatzmann Garcia, Cybele C Quintana, Francisco J Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity. 2021-12-08T19:24:39Z 2021-12-08T19:24:39Z 2020 2021-12-08T19:21:56Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138398 Giovannoni, Federico, Bosch, Irene, Polonio, Carolina Manganeli, Torti, María F, Wheeler, Michael A et al. 2020. "AHR is a Zika virus host factor and a candidate target for antiviral therapy." Nature Neuroscience, 23 (8). en 10.1038/S41593-020-0664-0 Nature Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Giovannoni, Federico Bosch, Irene Polonio, Carolina Manganeli Torti, María F Wheeler, Michael A Li, Zhaorong Romorini, Leonardo Rodriguez Varela, María S Rothhammer, Veit Barroso, Andreia Tjon, Emily C Sanmarco, Liliana M Takenaka, Maisa C Modaresi, Seyed Mohamad Sadegh Gutiérrez-Vázquez, Cristina Zanluqui, Nágela Ghabdan dos Santos, Nilton Barreto Munhoz, Carolina Demarchi Wang, Zhongyan Damonte, Elsa B Sherr, David Gehrke, Lee Peron, Jean Pierre Schatzmann Garcia, Cybele C Quintana, Francisco J AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title | AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title_full | AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title_fullStr | AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title_full_unstemmed | AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title_short | AHR is a Zika virus host factor and a candidate target for antiviral therapy |
| title_sort | ahr is a zika virus host factor and a candidate target for antiviral therapy |
| url | https://hdl.handle.net/1721.1/138398 |
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