Intrinsic antiviral immunity of barrier cells revealed by an iPSC-derived blood-brain barrier cellular model

• Published in: Cell reports (Cambridge) Vol. 39; no. 9; p. 110885
• Main Authors: Cheng, Yichen, Medina, Angelica, Yao, Zhenlan, Basu, Mausumi, Natekar, Janhavi P., Lang, Jianshe, Sanchez, Egan, Nkembo, Mezindia B., Xu, Chongchong, Qian, Xuyu, Nguyen, Phuong T.T., Wen, Zhexing, Song, Hongjun, Ming, Guo-Li, Kumar, Mukesh, Brinton, Margo A., Li, Melody M.H., Tang, Hengli
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.05.2022
• Subjects: Blood-Brain Barrier; blood-retinal barrier; blood-testis barrier; Brain - physiology; brain microvascular endothelial cell; dengue virus; Endothelial Cells - physiology; flavivirus; Humans; IFITM; Induced Pluripotent Stem Cells - physiology; intrinsic expression; Male; virus-host interactions; Zika virus; CP: Immunology; blood-brain barrier; IFITM; blood-retinal barrier; virus-host interactions; CP: Neuroscience; intrinsic expression; blood-testis barrier; dengue virus; Zika virus; brain microvascular endothelial cell; flavivirus
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110885

Physiological blood-tissue barriers play a critical role in separating the circulation from immune-privileged sites and denying access to blood-borne viruses. The mechanism of virus restriction by these barriers is poorly understood. We utilize induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (iBMECs) to study virus-blood-brain barrier (BBB) interactions. These iPSC-derived cells faithfully recapitulate a striking difference in in vivo neuroinvasion by two alphavirus isolates and are selectively permissive to neurotropic flaviviruses. A model of cocultured iBMECs and astrocytes exhibits high transendothelial electrical resistance and blocks non-neurotropic flaviviruses from getting across the barrier. We find that iBMECs constitutively express an interferon-induced gene, IFITM1, which preferentially restricts the replication of non-neurotropic flaviviruses. Barrier cells from blood-testis and blood-retinal barriers also constitutively express IFITMs that contribute to the viral resistance. Our application of a renewable human iPSC-based model for studying virus-BBB interactions reveals that intrinsic immunity at the barriers contributes to virus exclusion. [Display omitted] •iPSC-derived BBB cells recapitulate the in vivo phenotype of neuroinvasive viruses•An iBMEC/astrocyte coculture exhibits high TEER and models viral neuroinvasion•Constitutive expression of IFITM1 selectively inhibits non-neurotropic flaviviruses•Intrinsic expression of IFITMs contributes to broad barrier-based virus restriction Using a stem cell-derived cellular model and a panel of human pathogenic viruses, Cheng et al. show a mechanism by which some viruses can penetrate the blood-brain barrier and cause diseases in the central nervous system.