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

被引：75

作者：

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 ^{[6
,8
]}

dos Santos, Nilton Barreto ^{[9
]}

Munhoz, Carolina Demarchi ^{[9
]}

Wang, Zhongyan ^{[10
]}

Damonte, Elsa B. ^{[2
]}

Sherr, David ^{[10
]}

Gehrke, Lee ^{[3
,11
]}

Schatzmann Peron, Jean Pierre ^{[5
,6
,8
]}

Garcia, Cybele C. ^{[2
]}

Quintana, Francisco J. ^{[1
,12
]}

机构：

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

[4] Mt Sinai Sch Med, Dept Med, New York, NY USA

[5] Univ Sao Paulo, ICB 4, Immunol Dept, Neuroimmune Interact Lab, Sao Paulo, Brazil

[6] Univ Sao Paulo, Sci Platform Pasteur, 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

来源：

NATURE NEUROSCIENCE | 2020年 / 23卷 / 08期

基金：

巴西圣保罗研究基金会; 美国国家卫生研究院;

关键词：

ARYL-HYDROCARBON RECEPTOR; PROMYELOCYTIC LEUKEMIA PROTEIN; DENGUE; CELLS; INTERFERON; RESISTANCE; BRAZIL; MICE; RNA;

D O I：

10.1038/s41593-020-0664-0

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：939 / +

页数：28

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