RT Journal Article
SR Electronic
T1 Allelic Variation in the Toll-Like Receptor Adaptor Protein <em>Ticam2</em> Contributes to SARS-Coronavirus Pathogenesis in Mice
JF G3: Genes|Genomes|Genetics
FD Genetics Society of America
SP 1653
OP 1663
DO 10.1534/g3.117.041434
VO 7
IS 6
A1 Gralinski, Lisa E.
A1 Menachery, Vineet D.
A1 Morgan, Andrew P.
A1 Totura, Allison L.
A1 Beall, Anne
A1 Kocher, Jacob
A1 Plante, Jessica
A1 Harrison-Shostak, D. Corinne
A1 Schäfer, Alexandra
A1 Pardo-Manuel de Villena, Fernando
A1 Ferris, Martin T.
A1 Baric, Ralph S.
YR 2017
UL http://www.g3journal.org/content/7/6/1653.abstract
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. 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.