Browse by author
Lookup NU author(s): Dr Aidan Hanrath, Catherine Hatton, Dr Florian Gothe, Connie Browne, Dr Simon CockellORCiD, Professor Sophie Hambleton, 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.
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
URL: https://doi.org/10.3389/fimmu.2022.1035532
DOI: 10.3389/fimmu.2022.1035532
Altmetrics provided by Altmetric
