Journal Article

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

James, William S., Duncan, Christopher J. A., Cowley, Sally A., Vowles, Jane, Hanrath, Aidan T., Hambleton, Sophie, Gothe, Florian, Hatton, Catherine F., Browne, Cathy, Leary, Peter, Cockell, Simon J.

2022

Overview

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 cell (iPSC)-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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Animals / Antiviral Agents - therapeutic use / Cell death / Central nervous system / Cloning / Cytokines / Experiments / Flow cytometry / Guillain-Barre syndrome / Humans / IFNAR2 deficiency / Immune response / Immunity (Disease) / Immunology / inborn errors of immunity / Induced Pluripotent Stem Cells - metabolism / Infections / Innate immunity / Interferon / Interferons - pharmacology / Macrophages / Macrophages - metabolism / Microcephaly / Microglia / Microglia - metabolism / Pathogenesis / Pathogens / Pluripotency / Proteins / Receptor, Interferon alpha-beta - genetics / Replication / Stem cells / type I interferons / Vaccines / Zika Virus / Zika Virus Infection