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Type I Interferon receptor (IFNAR2) deficiency reveals Zika virus cytopathicity in human macrophages and microglia

Lookup NU author(s): Dr Aidan Hanrath, Catherine Hatton, Dr Florian Gothe, Connie Browne, Dr Simon CockellORCiD, Professor Sophie HambletonORCiD, Dr Christopher DuncanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Macrophages are key target cells of Zika virus (ZIKV) infection, implicated as a viral reservoir seeding sanctuary sites such as the central nervous system and testes. This rests on the apparent ability of macrophages to sustain ZIKV replication without experiencing cytopathic effects. ZIKV infection of macrophages triggers an innate immune response involving type I interferons (IFN-I), key antiviral cytokines that play a complex role in ZIKV pathogenesis in animal models. To investigate the functional role of the IFN-I response we generated human induced pluripotent stem (iPS) cell-derived macrophages from a patient with complete deficiency of IFNAR2, the high affinity IFN-I receptor subunit. Accompanying the profound defect of IFN-I signalling in IFNAR2 deficient iPS-macrophages we observed significantly enhanced ZIKV replication and cell death, revealing the inherent cytopathicity of ZIKV towards macrophages. These observations were recapitulated by genetic and pharmacological ablation of IFN-I signalling in control iPS-macrophages and extended to a model of iPS-microglia. Thus, the capacity of macrophages to support noncytolytic ZIKV replication depends on an equilibrium set by IFN-I, suggesting that innate antiviral responses might counterintuitively promote ZIKV persistence via the maintenance of tissue viral reservoirs relevant to pathogenesis.

Publication metadata

Author(s): Hanrath AT, Hatton CF, Gothe F, Browne C, Vowles J, Leary P, Cockell SJ, Cowley SA, James WS, Hambleton S, Duncan CJA

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2022

Volume: 13

Online publication date: 11/11/2022

Acceptance date: 21/10/2022

Date deposited: 02/11/2022

ISSN (electronic): 1664-3224

Publisher: Frontiers Research Foundation


DOI: 10.3389/fimmu.2022.1035532


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Funder referenceFunder name
207556/Z/17/ZWellcome Trust
211153/Z/18/ZWellcome Trust
the British Medical Association Foundation
the Bubble Foundation
the Care-for-Rare Foundation
the Munich Clinician Scientist Program at LMU (FoeFoLeplus)