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.
[1]Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Anat, Shanghai 200032, Peoples R China;
[2]Key Lab Med Imaging Comp & Comp Assisted Interven, Shanghai 200032, Peoples R China;
[3]Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China;
[4]Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China;
[5]Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China;
[6]Peking Univ, Beijing Key Lab Cardiometabol Mol Med, Inst Mol Med, Beijing 100871, Peoples R China
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