Mapping of susceptibility loci for Ebola virus pathogenesis in mice

Alexandra Schäfer; Andrea Marzi; Wakako Furuyama; Nicholas J Catanzaro; Cameron Nguyen; Elaine Haddock; Friederike Feldmann; Kimberly Meade-White; Tina Thomas; Miranda L Hubbard; Kendra L Gully; Sarah R Leist; Pablo Hock; Timothy A Bell; Gabriela E De la Cruz; Bentley R Midkiff; David R Martinez; Ginger D Shaw; Darla R Miller; Michael J Vernon; Rachel L Graham; Dale O Cowley; Stephanie A Montgomery; Klaus Schughart; Fernando Pardo Manuel de Villena; Gregory K Wilkerson; Martin T Ferris; Heinz Feldmann; Ralph S Baric

doi:10.1016/j.celrep.2024.114127

Mapping of susceptibility loci for Ebola virus pathogenesis in mice

Cell Rep. 2024 Apr 21;43(5):114127. doi: 10.1016/j.celrep.2024.114127. Online ahead of print.

Authors

Alexandra Schäfer¹, Andrea Marzi², Wakako Furuyama³, Nicholas J Catanzaro⁴, Cameron Nguyen⁴, Elaine Haddock³, Friederike Feldmann⁵, Kimberly Meade-White³, Tina Thomas⁵, Miranda L Hubbard⁴, Kendra L Gully⁴, Sarah R Leist⁴, Pablo Hock⁶, Timothy A Bell⁶, Gabriela E De la Cruz⁷, Bentley R Midkiff⁷, David R Martinez⁴, Ginger D Shaw⁶, Darla R Miller⁶, Michael J Vernon⁸, Rachel L Graham⁴, Dale O Cowley⁹, Stephanie A Montgomery¹⁰, Klaus Schughart¹¹, Fernando Pardo Manuel de Villena⁸, Gregory K Wilkerson¹⁰, Martin T Ferris⁶, Heinz Feldmann³, Ralph S Baric¹²

Affiliations

¹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: aschaefe@email.unc.edu.
² Laboratory of Virology, Division of Intramural Research, NIAID, NIH, Hamilton, MT 59840, USA. Electronic address: marzia@niaid.nih.gov.
³ Laboratory of Virology, Division of Intramural Research, NIAID, NIH, Hamilton, MT 59840, USA.
⁴ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Rocky Mountain Veterinary Branch, Division of Intramural Research, NIAID, NIH, Hamilton, MT 59840, USA.
⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁹ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Animal Models Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Institute of Virology, University of Muenster, 48149 Muenster, Germany.
¹² Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: rbaric@email.unc.edu.

PMID: 38652660
DOI: 10.1016/j.celrep.2024.114127

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.

Keywords: CP: Immunology; CP: Microbiology; Ebola virus disease (EVD); QTL; Trim5 locus; collaborative cross mice; filovirus; host response; liver damage.