Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice

E. Gralinski, Vineet Menachery, Andrew P. Morgan, Allison L. Totura, Anne Beall, Jacob Kocher, Jessica Plante, D. Corinne Harrison-Shostak, Alexandra Schäfer, Fernando Pardo Manuel Villena, Martin T. Ferris, Ralph S. Baric

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam22/2 mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.

Original languageEnglish (US)
Pages (from-to)1653-1663
Number of pages11
JournalG3: Genes, Genomes, Genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Fingerprint

SARS Virus
Toll-Like Receptors
Severe Acute Respiratory Syndrome
Coronavirus
Weight Loss
Hemorrhage
Quantitative Trait Loci
Proteins
Viral Load
Coronavirus Infections
Phenotype
Chromosomes, Human, Pair 18
Lung
Infection
Population

Keywords

  • Collaborative Cross
  • F2
  • Host susceptibility genes
  • MPP
  • Multi-parent Advanced Generation Inter- Cross (MAGIC)
  • Multiparental populations
  • SARS-CoV
  • Ticam2

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice. / Gralinski, E.; Menachery, Vineet; Morgan, Andrew P.; Totura, Allison L.; Beall, Anne; Kocher, Jacob; Plante, Jessica; Harrison-Shostak, D. Corinne; Schäfer, Alexandra; Villena, Fernando Pardo Manuel; Ferris, Martin T.; Baric, Ralph S.

In: G3: Genes, Genomes, Genetics, Vol. 7, No. 6, 01.06.2017, p. 1653-1663.

Research output: Contribution to journalArticle

Gralinski, E, Menachery, V, Morgan, AP, Totura, AL, Beall, A, Kocher, J, Plante, J, Harrison-Shostak, DC, Schäfer, A, Villena, FPM, Ferris, MT & Baric, RS 2017, 'Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice', G3: Genes, Genomes, Genetics, vol. 7, no. 6, pp. 1653-1663. https://doi.org/10.1534/g3.117.041434
Gralinski, E. ; Menachery, Vineet ; Morgan, Andrew P. ; Totura, Allison L. ; Beall, Anne ; Kocher, Jacob ; Plante, Jessica ; Harrison-Shostak, D. Corinne ; Schäfer, Alexandra ; Villena, Fernando Pardo Manuel ; Ferris, Martin T. ; Baric, Ralph S. / Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice. In: G3: Genes, Genomes, Genetics. 2017 ; Vol. 7, No. 6. pp. 1653-1663.
@article{9fabb5345ff544909e9adfc1f2a16d8a,
title = "Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice",
abstract = "Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam22/2 mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.",
keywords = "Collaborative Cross, F2, Host susceptibility genes, MPP, Multi-parent Advanced Generation Inter- Cross (MAGIC), Multiparental populations, SARS-CoV, Ticam2",
author = "E. Gralinski and Vineet Menachery and Morgan, {Andrew P.} and Totura, {Allison L.} and Anne Beall and Jacob Kocher and Jessica Plante and Harrison-Shostak, {D. Corinne} and Alexandra Sch{\"a}fer and Villena, {Fernando Pardo Manuel} and Ferris, {Martin T.} and Baric, {Ralph S.}",
year = "2017",
month = "6",
day = "1",
doi = "10.1534/g3.117.041434",
language = "English (US)",
volume = "7",
pages = "1653--1663",
journal = "G3: Genes, Genomes, Genetics",
issn = "2160-1836",
publisher = "Genetics Society of America",
number = "6",

}

TY - JOUR

T1 - Allelic variation in the toll-like receptor adaptor protein Ticam2 contributes to SARS-coronavirus pathogenesis in mice

AU - Gralinski, E.

AU - Menachery, Vineet

AU - Morgan, Andrew P.

AU - Totura, Allison L.

AU - Beall, Anne

AU - Kocher, Jacob

AU - Plante, Jessica

AU - Harrison-Shostak, D. Corinne

AU - Schäfer, Alexandra

AU - Villena, Fernando Pardo Manuel

AU - Ferris, Martin T.

AU - Baric, Ralph S.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam22/2 mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.

AB - Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam22/2 mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses.

KW - Collaborative Cross

KW - F2

KW - Host susceptibility genes

KW - MPP

KW - Multi-parent Advanced Generation Inter- Cross (MAGIC)

KW - Multiparental populations

KW - SARS-CoV

KW - Ticam2

UR - http://www.scopus.com/inward/record.url?scp=85020271369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020271369&partnerID=8YFLogxK

U2 - 10.1534/g3.117.041434

DO - 10.1534/g3.117.041434

M3 - Article

VL - 7

SP - 1653

EP - 1663

JO - G3: Genes, Genomes, Genetics

JF - G3: Genes, Genomes, Genetics

SN - 2160-1836

IS - 6

ER -