Intrinsic antiviral immunity of barrier cells revealed by an iPSC-derived blood-brain barrier cellular model
Yichen Cheng, Angelica Medina, Zhenlan Yao, Mausumi Basu, Janhavi P. Natekar, Jianshe Lang, Egan Sanchez, Mezindia B. Nkembo, Chongchong Xu, Xuyu Qian, Phuong Nguyen, Zhexing Wen, Hongjun Song, Guo‐li Ming, Mukesh Kumar, Margo A. Brinton, Melody M. H. Li, Hengli Tang
Abstract
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.