Abstract
Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) poses a serious threat to the world’s public health yet without a cure. Certain JEV-infected neural cells express a subset of previously identified intrinsic antiviral interferon stimulated genes (ISGs), indicating brain cells retain autonomous antiviral immunity. However, whether this happens in composited brain remains unclear. Human pluripotent stem cell (hPSC)-derived organoids can model disorders caused by human endemic pathogens such as Zika virus, which may potentially address this question and facilitate the discovery of a cure for JE. We thus generated telencephalon organoid and infected them with JEV. We found JEV infection caused significant decline of cell proliferation and increase of cell death in brain organoid, resulting in smaller organoid spheres. JEV tended to infect astrocytes and neural progenitors, especially the population representing outer radial glial cells (oRGCs) of developing human brain. In addition, we revealed variable antiviral immunity in brain organoids of different stages of culture. In organoids of longer culture (older than 8 weeks), but not of early ones (less than 4 weeks), JEV infection caused typical activation of interferon signaling pathway. Preferential infection of oRGCs and differential antiviral response at various stages might explain the much more severe outcomes of JEV infection in the younger, which also provide clues to develop effective therapeutics of such diseases.
Highlights
Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) is one of the most common viral inflammation diseases, in wide area of Asia
Telencephalon cortical organoids derived from other human embryonic stem cell (hESC) lines such as Q-CTS-hESC-127 exhibit multiple progenitor zones at day 45 (Supplementary Fig. 1d)
JEV infection causes irreversible brain damage, which remains a challenging issue across the world[38]
Summary
Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) is one of the most common viral inflammation diseases, in wide area of Asia. JE occurs primarily among children aged less than 10 years. JEV infection induces non-cell necrotic plaques accompanied by nodules of glia, edema, bleeding, and inflammatory infiltration in multiple brain. JE, no effective cure is available for the JEV-infected patients. JE remains one of the most serious threats to public health[6]. During JEV infection, proinflammatory cytokines and chemokines concertedly trigger neuronal damages. In vitro assays indicate that JEV preferentially infects neural precursor cells and glial cells, rather than neurons[7]
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