Host Genetic Diversity Enables Ebola Hemorrhagic Fever Pathogenesis and Resistance

Overview

Journal Science

Specialty Science

Date 2014 Nov 1

PMID 25359852

Citations 168

Authors

Angela L Rasmussen

Atsushi Okumura

Martin T Ferris

Richard Green

Friederike Feldmann

Sara M Kelly

Dana P Scott

David Safronetz

Elaine Haddock

Rachel LaCasse

Matthew J Thomas

Pavel Sova

Victoria S Carter

Jeffrey M Weiss

Darla R Miller

Ginger D Shaw

Marcus J Korth

Mark T Heise

Ralph S Baric

Fernando Pardo-Manuel de Villena

Heinz Feldmann

Michael G Katze

Affiliations

Soon will be listed here.

Abstract

Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.

Citing Articles

Analysis of Hepatic Lentiviral Vector Transduction: Implications for Preclinical Studies and Clinical Gene Therapy Protocols.

Hu P, Hao Y, Tang W, Diering G, Zou F, Kafri T Viruses. 2025; 17(2).

PMID: 40007031 PMC: 11861806. DOI: 10.3390/v17020276.

Virus Load Kinetics in Lassa Fever Patients Treated With Ribavirin: A Retrospective Cohort Study From Southern Nigeria.

Ogbaini-Emovon E, Akpede G, Okogbenin S, Osagiede E, Tobin E, Asogun D Open Forum Infect Dis. 2024; 11(10):ofae575.

PMID: 39450398 PMC: 11500659. DOI: 10.1093/ofid/ofae575.

Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19.

Baker C, Duso D, Kothapalli N, Hart T, Casey S, Cookenham T Sci Rep. 2024; 14(1):25147.

PMID: 39448712 PMC: 11502910. DOI: 10.1038/s41598-024-77087-1.

Emerging and reemerging infectious diseases: global trends and new strategies for their prevention and control.

Wang S, Li W, Wang Z, Yang W, Li E, Xia X Signal Transduct Target Ther. 2024; 9(1):223.

PMID: 39256346 PMC: 11412324. DOI: 10.1038/s41392-024-01917-x.

Analysis of hepatic lentiviral vector transduction; implications for preclinical studies and clinical gene therapy protocols.

Hu P, Hao Y, Tang W, Diering G, Zou F, Kafri T bioRxiv. 2024; .

PMID: 39229157 PMC: 11370356. DOI: 10.1101/2024.08.20.608805.

References

Yang H, Wang J, Didion J, Buus R, Bell T, Welsh C . Subspecific origin and haplotype diversity in the laboratory mouse. Nat Genet. 2011; 43(7):648-55. PMC: 3125408. DOI: 10.1038/ng.847. View

Dixon M, Schafer I . Ebola viral disease outbreak--West Africa, 2014. MMWR Morb Mortal Wkly Rep. 2014; 63(25):548-51. PMC: 5779383. View

Roberts A, Pardo-Manuel de Villena F, Wang W, McMillan L, Threadgill D . The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm Genome. 2007; 18(6-7):473-81. PMC: 1998888. DOI: 10.1007/s00335-007-9045-1. View

Sato T, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gridley T . Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995; 376(6535):70-4. DOI: 10.1038/376070a0. View

Groseth A, Marzi A, Hoenen T, Herwig A, Gardner D, Becker S . The Ebola virus glycoprotein contributes to but is not sufficient for virulence in vivo. PLoS Pathog. 2012; 8(8):e1002847. PMC: 3410889. DOI: 10.1371/journal.ppat.1002847. View

Yen J, Garamszegi S, Geisbert J, Rubins K, Geisbert T, Honko A . Therapeutics of Ebola hemorrhagic fever: whole-genome transcriptional analysis of successful disease mitigation. J Infect Dis. 2011; 204 Suppl 3:S1043-52. DOI: 10.1093/infdis/jir345. View

Bottomly D, Ferris M, Aicher L, Rosenzweig E, Whitmore A, Aylor D . Expression quantitative trait Loci for extreme host response to influenza a in pre-collaborative cross mice. G3 (Bethesda). 2012; 2(2):213-21. PMC: 3284329. DOI: 10.1534/g3.111.001800. View

Nolan V, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski D . Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol. 2006; 133(5):570-8. PMC: 1679888. DOI: 10.1111/j.1365-2141.2006.06074.x. View

Leroy E, Baize S, Mavoungou E, Apetrei C . Sequence analysis of the GP, NP, VP40 and VP24 genes of Ebola virus isolated from deceased, surviving and asymptomatically infected individuals during the 1996 outbreak in Gabon: comparative studies and phylogenetic characterization. J Gen Virol. 2001; 83(Pt 1):67-73. DOI: 10.1099/0022-1317-83-1-67. View

10.

Strong J, Wong G, Jones S, Grolla A, Theriault S, Kobinger G . Stimulation of Ebola virus production from persistent infection through activation of the Ras/MAPK pathway. Proc Natl Acad Sci U S A. 2008; 105(46):17982-7. PMC: 2577702. DOI: 10.1073/pnas.0809698105. View

11.

Ebihara H, Zivcec M, Gardner D, Falzarano D, LaCasse R, Rosenke R . A Syrian golden hamster model recapitulating ebola hemorrhagic fever. J Infect Dis. 2012; 207(2):306-18. PMC: 3532827. DOI: 10.1093/infdis/jis626. View

12.

Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N . Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med. 2014; 371(15):1418-25. DOI: 10.1056/NEJMoa1404505. View

13.

Ferris M, Aylor D, Bottomly D, Whitmore A, Aicher L, Bell T . Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog. 2013; 9(2):e1003196. PMC: 3585141. DOI: 10.1371/journal.ppat.1003196. View

14.

Ebihara H, Takada A, Kobasa D, Jones S, Neumann G, Theriault S . Molecular determinants of Ebola virus virulence in mice. PLoS Pathog. 2006; 2(7):e73. PMC: 1513261. DOI: 10.1371/journal.ppat.0020073. View

15.

Brouillard P, Olsen B, Vikkula M . High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics. 2000; 67(1):96-101. DOI: 10.1006/geno.2000.6232. View

16.

Flanagan J, Frohlich D, Howard T, Schultz W, Driscoll C, Nagasubramanian R . Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011; 117(24):6681-4. PMC: 3123027. DOI: 10.1182/blood-2011-01-332205. View

17.

Vikkula M, Boon L, Carraway 3rd K, Calvert J, Diamonti A, Goumnerov B . Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996; 87(7):1181-90. DOI: 10.1016/s0092-8674(00)81814-0. View

18.

Zheng Q, Du J, Zhang Z, Xu J, Fu L, Cao Y . Association study between of Tie2/angiopoietin-2 and VEGF/KDR pathway gene polymorphisms and vascular malformations. Gene. 2013; 523(2):195-8. DOI: 10.1016/j.gene.2013.02.053. View

19.

Leroy E, Baize S, Volchkov V, Fisher-Hoch S, Georges-Courbot M, Capron M . Human asymptomatic Ebola infection and strong inflammatory response. Lancet. 2000; 355(9222):2210-5. DOI: 10.1016/s0140-6736(00)02405-3. View

20.

Bray M, Hatfill S, Hensley L, Huggins J . Haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus. J Comp Pathol. 2002; 125(4):243-53. DOI: 10.1053/jcpa.2001.0503. View