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

Autor(es):Mostrar menos -

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]}

Afiliação do(s) autor(es):Mostrar menos -

^[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

• Tipo de documento: Artigo Científico
• Fonte: NATURE NEUROSCIENCE; v. 23, n. 8 JUL 2020.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 17/26170-0 - Neuroimunobiologia em modelo experimental de Encefalomielite Autoimune e Síndrome Congênita do Zika Vírus: fisiopatogenia, susceptibilidade, terapia celular, vacinação
• Beneficiário: Jean Pierre Schatzmann Peron
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/11828-0 - "Avaliação do papel dos microRNAs na imunopatogênese da microcefalia causada pelo Zika vírus em modelos experimentais"
• Beneficiário: Carolina Manganeli Polonio
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/22504-1 - O papel dos receptores TAM e seus ligantes, Gas6 e Pros1, na Síndrome Congênita do Zika Vírus Experimental
• Beneficiário: Jean Pierre Schatzmann Peron
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/07371-2 - "caracterização do papel de linfócitos t cd8+ na infecção por zika vírus"
• Beneficiário: Nagela Ghabdan Zanluqui
• Linha de fomento: Bolsas no Brasil - Doutorado