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Allelic Variation in the Toll-Like Receptor Adaptor Protein
- Source :
- G3: Genes|Genomes|Genetics
- Publication Year :
- 2017
-
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. Ticam2−/− 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.
- Subjects :
- Male
MPP
Genotype
Ticam2
host susceptibility genes
Quantitative Trait Loci
Severe Acute Respiratory Syndrome
Collaborative Cross
Cell Line
Mice
Multiparental Populations
Animals
Genetic Predisposition to Disease
Multi-parent Advanced Generation Inter-Cross (MAGIC)
Alleles
Mice, Knockout
Chromosome Mapping
Genetic Variation
SARS-CoV
Viral Load
F2
Disease Models, Animal
Phenotype
Severe acute respiratory syndrome-related coronavirus
Host-Pathogen Interactions
Female
Subjects
Details
- ISSN :
- 21601836
- Volume :
- 7
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- G3 (Bethesda, Md.)
- Accession number :
- edsair.pmid..........c38bdc1b43f64e1df0cf16e17c06feb1