Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (27), p.7117-7122
• Main Authors: Muffat, Julien, Li, Yun, Omer, Attya, Durbin, Ann, Bosch, Irene, Bakiasi, Grisilda, Richards, Edward, Meyer, Aaron, Gehrke, Lee, Jaenisch, Rudolf
• Format: Article
• Language: English
• Subjects: Angiogenesis; Astrocytes; Biological Sciences; Brain; Central nervous system; Cytotoxicity; Dengue fever; Epidemics; Female; Fetuses; Glial cells; Glial stem cells; Humans; Immune response; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Induced Pluripotent Stem Cells - virology; Infections; Macrophages; Microcephaly; Microencephaly; Microglia; Nervous system; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neural Stem Cells - virology; Neuroglia - metabolism; Neuroglia - pathology; Neuroglia - virology; Neuronal-glial interactions; Pluripotency; Pregnancy; Pregnancy Complications, Infectious - metabolism; Pregnancy Complications, Infectious - pathology; Spheroids; Stem cells; Teratogenicity; Tropism; Vector-borne diseases; Viral diseases; Viral infections; Viruses; Zika virus; Zika Virus - metabolism; Zika Virus Infection - metabolism; Zika Virus Infection - pathology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1719266115

Maternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood–brain barrier, thus allowing infection of the brain later in life.