1. Mapping of susceptibility loci for Ebola virus pathogenesis in mice.
- Author
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Schäfer A, Marzi A, Furuyama W, Catanzaro NJ, Nguyen C, Haddock E, Feldmann F, Meade-White K, Thomas T, Hubbard ML, Gully KL, Leist SR, Hock P, Bell TA, De la Cruz GE, Midkiff BR, Martinez DR, Shaw GD, Miller DR, Vernon MJ, Graham RL, Cowley DO, Montgomery SA, Schughart K, de Villena FPM, Wilkerson GK, Ferris MT, Feldmann H, and Baric RS
- Subjects
- Animals, Mice, Mice, Knockout, Chromosome Mapping, Liver pathology, Liver metabolism, Humans, Mice, Inbred C57BL, Female, Male, Hemorrhagic Fever, Ebola virology, Hemorrhagic Fever, Ebola genetics, Hemorrhagic Fever, Ebola pathology, Quantitative Trait Loci genetics, Ebolavirus pathogenicity, Ebolavirus genetics, Genetic Predisposition to Disease
- Abstract
Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies., Competing Interests: Declaration of interests D.O.C. is employed by, has equity ownership in, and serves on the board of directors of TransViragen, the company that has been contracted by UNC-Chapel Hill to manage its Animal Models Core Facility. R.S.B. is a member of advisory boards for VaxArt, Takeda, and Invivyd, focused on unrelated projects., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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