Allelic Variation in the Toll-Like Receptor Adaptor Protein

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Gralinski, Lisa
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Menachery, Vineet D.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Morgan, Andrew P.
- Affiliation: School of Medicine, Department of Genetics
Totura, Allison L.
- Affiliation: School of Medicine, Department of Microbiology and Immunology
Beall, Anne
- Affiliation: School of Medicine, Department of Genetics
Kocher, Jacob
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Plante, Jessica
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Harrison-Shostak, D. Corinne
- Affiliation: School of Medicine, Department of Genetics
Schäfer, Alexandra
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Villena, Fernando Pardo-Manuel
- Affiliation: School of Medicine, Department of Genetics
- Other Affiliation: University of North Carolina at Chapel Hill
Ferris, Martin T.
- Affiliation: School of Medicine, Department of Genetics
Baric, Ralph S.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
- Other Affiliation: University of North Carolina at Chapel Hill

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.

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