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

Jul 23, 2020

Contributor: Federico Giovannoni,Irene Bosch,Carolina Manganeli Polonio,María F Torti,Michael A Wheeler,Zhaorong Li,Leonardo Romorini,María S Rodriguez Varela,Veit Rothhammer,Andreia Barroso,Emily C Tjon,Liliana M Sanmarco,Maisa C Takenaka,Seyed Mohamad Sadegh Modaresi,Cristina Gutiérrez-Vázquez,Nágela Ghabdan Zanluqui,Nilton Barreto Dos Santos,Carolina Demarchi Munhoz,Zhongyan Wang,Elsa B Damonte,David Sherr,Lee Gehrke,Jean Pierre Schatzmann Peron,Cybele C Garcia,Francisco J Quintana

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 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.

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About The Expert

Federico Giovannoni

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Laboratorio de Estrategias Antivirales, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. CONICET-Instituto de Química Biológica, Buenos Aires, Argentina.

Irene Bosch

Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.

Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.

Carolina Manganeli Polonio

Neuroimmune Interactions Laboratory, Immunology Department-ICB IV, University of São Paulo, São Paulo, Brazil.

Scientific Platform Pasteur-USP, University of São Paulo, São Paulo, Brazil.

María F Torti

Laboratorio de Estrategias Antivirales, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. CONICET-Instituto de Química Biológica, Buenos Aires, Argentina.

Michael A Wheeler

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Zhaorong Li

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Leonardo Romorini

Laboratorio de Investigación aplicada a Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Buenos Aires, Argentina.

María S Rodriguez Varela

Laboratorio de Investigación aplicada a Neurociencias, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Buenos Aires, Argentina.

Veit Rothhammer

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Andreia Barroso

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Emily C Tjon

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Liliana M Sanmarco

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Maisa C Takenaka

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Seyed Mohamad Sadegh Modaresi

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Cristina Gutiérrez-Vázquez

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Nágela Ghabdan Zanluqui

Scientific Platform Pasteur-USP, University of São Paulo, São Paulo, Brazil.

Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo, Brazil.

Nilton Barreto Dos Santos

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.

Carolina Demarchi Munhoz

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.

Zhongyan Wang

Dept. of Environmental Health, Boston University School of Public Health, Boston, MA, USA.

Elsa B Damonte

Laboratorio de Estrategias Antivirales, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. CONICET-Instituto de Química Biológica, Buenos Aires, Argentina.

David Sherr

Dept. of Environmental Health, Boston University School of Public Health, Boston, MA, USA.

Lee Gehrke

Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.

Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.

Jean Pierre Schatzmann Peron

Neuroimmune Interactions Laboratory, Immunology Department-ICB IV, University of São Paulo, São Paulo, Brazil. jeanpierre@usp.br.

Scientific Platform Pasteur-USP, University of São Paulo, São Paulo, Brazil. jeanpierre@usp.br.

Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo, Brazil. jeanpierre@usp.br.

Cybele C Garcia

Laboratorio de Estrategias Antivirales, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. CONICET-Instituto de Química Biológica, Buenos Aires, Argentina. cygarcia@qb.fcen.uba.ar.

Francisco J Quintana

Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.

Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.

References

PubMed