Frontiers in Immunology (May 2023)

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

  • Elise Van Breedam,
  • Tamariche Buyle-Huybrecht,
  • Tamariche Buyle-Huybrecht,
  • Tamariche Buyle-Huybrecht,
  • Jonas Govaerts,
  • Jonas Govaerts,
  • Jonas Govaerts,
  • Pieter Meysman,
  • Pieter Meysman,
  • Pieter Meysman,
  • Andrea Bours,
  • Marlies Boeren,
  • Marlies Boeren,
  • Marlies Boeren,
  • Julia Di Stefano,
  • Thalissa Caers,
  • Thalissa Caers,
  • Hans De Reu,
  • Hans De Reu,
  • Laura Dirkx,
  • Jolien Schippers,
  • Esther Bartholomeus,
  • Marielle Lebrun,
  • Catherine Sadzot-Delvaux,
  • Paulina Rybakowska,
  • Marta E. Alarcón-Riquelme,
  • Concepción Marañón,
  • Kris Laukens,
  • Kris Laukens,
  • Kris Laukens,
  • Peter Delputte,
  • Peter Delputte,
  • Benson Ogunjimi,
  • Benson Ogunjimi,
  • Benson Ogunjimi,
  • Benson Ogunjimi,
  • Peter Ponsaerts,
  • Peter Ponsaerts

DOI
https://doi.org/10.3389/fimmu.2023.1177245
Journal volume & issue
Vol. 14

Abstract

Read online

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.

Keywords