AHR is a Zika virus host factor and a candidate target for antiviral therapy

Author(s):Show less -

Giovannoni, Federico ^{[1, 2]} ; Bosch, Irene ^{[3, 4]} ; Polonio, Carolina Manganeli ^{[5, 6]} ; Torti, Maria F. ^[2] ; Wheeler, Michael A. ^[1] ; Li, Zhaorong ^[1] ; Romorini, Leonardo ^[7] ; Rodriguez Varela, Maria S. ^[7] ; Rothhammer, Veit ^[1] ; Barroso, Andreia ^[1] ; Tjon, Emily C. ^[1] ; Sanmarco, Liliana M. ^[1] ; Takenaka, Maisa C. ^[1] ; Modaresi, Seyed Mohamad Sadegh ^[1] ; Gutierrez-Vazquez, Cristina ^[1] ; Zanluqui, Nagela Ghabdan ^{[5, 8]} ; dos Santos, Nilton Barreto ^[9] ; Munhoz, Carolina Demarchi ^[9] ; Wang, Zhongyan ^[10] ; Damonte, Elsa B. ^[2] ; Sherr, David ^[10] ; Gehrke, Lee ^{[11, 4]} ; Schatzmann Peron, Jean Pierre ^{[5, 8, 6]} ; Garcia, Cybele C. ^[2] ; Quintana, Francisco J. ^{[12, 1]}

Affiliation:Show less -

^[1] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 - USA

^[2] Univ Buenos Aires, CONICET, Inst Quim Biol, Fac Ciencias Exactas & Nat, Dept Quim Biol, Lab Est, Buenos Aires, DF - Argentina

^[3] Mt Sinai Sch Med, Dept Med, New York, NY - USA

^[4] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[5] Univ Sao Paulo, Sci Platform Pasteur, Sao Paulo - Brazil

^[6] Univ Sao Paulo, ICB 4, Immunol Dept, Neuroimmune Interact Lab, Sao Paulo - Brazil

^[7] Fdn Lucha Enfermedades Neurol Infancia, Lab Invest Aplicada Neurociencias, Buenos Aires, DF - Argentina

^[8] Univ Sao Paulo, Sch Med, Immunopathol & Allergy Post Grad Program, Sao Paulo - Brazil

^[9] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[10] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA - USA

^[11] Harvard Med Sch, Div Med Sci, Program Virol, Boston, MA 02115 - USA

^[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 - USA

• Document type: Journal article
• Source: NATURE NEUROSCIENCE; v. 23, n. 8 JUL 2020.
• Web of Science Citations: 1

Abstract

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. Giovannoni et al. report that the aryl hydrocarbon receptor (AHR) is a novel host factor exploited by Zika virus and dengue virus to evade the immune response. AHR is a candidate target for the treatment of Zika virus congenital syndrome and dengue fever. (AU)

• FAPESP's process: 17/11828-0 - Evaluation of the microRNAs role in the immunopathogenesis of microcephaly caused by Zika virus in experimental models
• Grantee: Carolina Manganeli Polonio
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/22504-1 - TAM receptors and their ligands Gas6 and Pros1 on the ZIKV Congenital Syndrome in Experimental Models
• Grantee: Jean Pierre Schatzmann Peron
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07371-2 - Characterization of the role of T CD8+ lymphocytes in Zika virus infection
• Grantee: Nagela Ghabdan Zanluqui
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/26170-0 - Neuroimmunology in experimental models of Autoimmune Encephalomyelitis and Congenital Zika Syndrome: physiopathogenesis, susceptibility, cellular therapy, vaccination
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Research Projects - Thematic Grants