학술논문
Lack of strong innate immune reactivity renders macrophages alone unable to control productive Varicella-Zoster Virus infection in an isogenic human iPSC-derived neuronal co-culture model
Document Type
article
Author
Elise Van Breedam; Tamariche Buyle-Huybrecht; Jonas Govaerts; Pieter Meysman; Andrea Bours; Marlies Boeren; Julia Di Stefano; Thalissa Caers; Hans De Reu; Laura Dirkx; Jolien Schippers; Esther Bartholomeus; Marielle Lebrun; Catherine Sadzot-Delvaux; Paulina Rybakowska; Marta E. Alarcón-Riquelme; Concepción Marañón; Kris Laukens; Peter Delputte; Benson Ogunjimi; Peter Ponsaerts
Source
Frontiers in Immunology, Vol 14 (2023)
Subject
Language
English
ISSN
1664-3224
Abstract
With Varicella-Zoster Virus (VZV) being an exclusive human pathogen, human induced pluripotent stem cell (hiPSC)-derived neural cell culture models are an emerging tool to investigate VZV neuro-immune interactions. Using a compartmentalized hiPSC-derived neuronal model allowing axonal VZV infection, we previously demonstrated that paracrine interferon (IFN)-α2 signalling is required to activate a broad spectrum of interferon-stimulated genes able to counteract a productive VZV infection in hiPSC-neurons. In this new study, we now investigated whether innate immune signalling by VZV-challenged macrophages was able to orchestrate an antiviral immune response in VZV-infected hiPSC-neurons. In order to establish an isogenic hiPSC-neuron/hiPSC-macrophage co-culture model, hiPSC-macrophages were generated and characterised for phenotype, gene expression, cytokine production and phagocytic capacity. Even though immunological competence of hiPSC-macrophages was shown following stimulation with the poly(dA:dT) or treatment with IFN-α2, hiPSC-macrophages in co-culture with VZV-infected hiPSC-neurons were unable to mount an antiviral immune response capable of suppressing a productive neuronal VZV infection. Subsequently, a comprehensive RNA-Seq analysis confirmed the lack of strong immune responsiveness by hiPSC-neurons and hiPSC-macrophages upon, respectively, VZV infection or challenge. This may suggest the need of other cell types, like T-cells or other innate immune cells, to (co-)orchestrate an efficient antiviral immune response against VZV-infected neurons.