Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice.
Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice.
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DOI：
10.1534/g3.117.041434
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发表时间：
2017-06-07
期刊：
影响因子：
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通讯作者：
Baric RS
中科院分区：
文献类型：
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作者：
Gralinski LE;Menachery VD;Morgan AP;Totura AL;Beall A;Kocher J;Plante J;Harrison-Shostak DC;Schäfer A;Pardo-Manuel de Villena F;Ferris MT;Baric RS
已知宿主遗传变异有助于感染后的不同发病机制。小鼠模型可以直接评估导致对严重急性呼吸综合征冠状病毒（SARS-CoV）易感性的宿主遗传因素。基于对来自协作杂交小鼠多亲本群体的早期品系的评估，我们确定了对SARS-CoV表现出高度不同敏感性的两个品系：耐药的CC003/Unc和易感的CC053/Unc。我们在这些菌株之间产生264只F2小鼠，并用SARS-CoV感染它们。体重减轻、肺出血和病毒载量都是高度相关的疾病表型。我们在18号染色体上发现了一个影响体重减轻、病毒滴度和出血的主要数量性状位点（27.1-58.6 Mb）。此外，这三种表型都有不同的数量性状位点[Chr 9（体重减轻），Chr 7和12（病毒滴度），Chr 15（出血）]。我们确定了TLR信号通路中的衔接蛋白Ticam2，作为Chr 18位点上驱动差异疾病的候选蛋白。与对照小鼠相比，Ticam2 - / -小鼠对SARS-CoV感染高度敏感，表现出体重减轻和肺出血的增加。这些结果表明，Ticam2在SARS-CoV疾病中发挥了关键作用，并强调了宿主遗传变异在疾病反应中的重要性。
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.