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

• Type of Material: Article
• Authors: Yichen Cheng, Florida State University; Angelica Medina, Florida State University; Zhenlan Yao, University of California Los Angeles; Mausumi Basu, Georgia State University; Janhavi P Natekar, Georgia State University; Jianshe Lang, Florida State University; Egan Sanchez, Florida State University; Mezindia B Nkembo, Florida State University; Chongchong Xu, Emory University; Xuyu Qian, University of Pennsylvania; Phuong TT Nguyen, University of Pennsylvania; Zhexing Wen, Emory University; Hongjun Song, University of Pennsylvania; Guo-Li Ming, University of Pennsylvania; Mukesh Kumar, Georgia State University; Margo A Brinton, Georgia State University; Melody MH Li, University of California Los Angeles; Hengli Tang, Florida State University
• Language: English
• Date: 2022-05-31
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2022.110885
• Title of Journal or Parent Work: CELL REPORTS
• Volume: 39
• Issue: 9
• Start Page: 110885
• End Page: 110885
• Grant/Funding Information: This study was supported by National Institutes of Health grants to H.T. (U19AI131130 and R01AI146342), M.M.H.L. (R01AI158704), M.A.B. (U19AI131130), M.K. (R21OD024896), G.M. (U19AI131130 and R35NS097370), and H.S. (R35NS116843).; M.M.H.L. is also supported by UCLA Broad Stem Cell Research Center (Research Award).
• Keywords: Life Sciences & Biomedicine; T-CELLS; ENDOTHELIAL-CELLS; Cell Biology; INFECTION; PROTEINS; WEST-NILE-VIRUS; ZIKA-VIRUS; SINDBIS VIRUS; IN-VITRO; ENCEPHALITIS-VIRUS; IFITM3 RESTRICTS; Science & Technology

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.