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

Frontiers in Immunology

Immunology

Esther Bartholomeus¹  Jolien Schippers¹  Benson Ogunjimi²  Pieter Meysman³  Kris Laukens³  Andrea Bours⁴  Peter Delputte⁵  Concepción Marañón⁶  Paulina Rybakowska⁶  Marta E. Alarcón-Riquelme⁶  Elise Van Breedam⁷  Julia Di Stefano⁷  Jonas Govaerts⁸  Marlies Boeren⁸  Tamariche Buyle-Huybrecht⁸  Hans De Reu⁹  Peter Ponsaerts⁹  Thalissa Caers^1,10  Laura Dirkx^1,11  Marielle Lebrun^1,12  Catherine Sadzot-Delvaux^1,12 

[1] Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium;Centre for Health Economics Research & Modelling Infectious Diseases (CHERMID), Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium;Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium;Adrem Data Lab, Department of Computer Science, University of Antwerp, Antwerp, Belgium;Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, Antwerp, Belgium;Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, Antwerp, Belgium;Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, Antwerp, Belgium;Infla-Med, University of Antwerp, Antwerp, Belgium;Department of Genomic Medicine, Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Junta de Andalucía, Parque Tecnológico de la Salud (PTS), Granada, Spain;Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium;Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Flow Cytometry and Cell Sorting Core Facility (FACSUA), Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium;Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium;Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium;Laboratory of Virology and Immunology, Interdisciplinary Research Institute in the Biomedical Sciences GIGA-Infection, Inflammation and Immunity, University of Liège, Liège, Belgium;

关键词: varicella zoster virus;    iPSC;    neurons;    macrophages;    neuronal models;    axonal infection;    innate immune response;    RNA-seq analysis;   

DOI  :  10.3389/fimmu.2023.1177245

 received in 2023-03-01, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Van Breedam, Buyle-Huybrecht, Govaerts, Meysman, Bours, Boeren, Di Stefano, Caers, De Reu, Dirkx, Schippers, Bartholomeus, Lebrun, Sadzot-Delvaux, Rybakowska, Alarcón-Riquelme, Marañón, Laukens, Delputte, Ogunjimi and Ponsaerts