Allelic Variation in the Toll-Like Receptor Adaptor ProteinTicam2Contributes 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. 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.

Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross

“…The CC and its founders have been used to successfully identify genetic association for several traits, including spontaneous colitis and susceptibility to infection by viruses such as Ebola, West Nile, Severe Acute Respiratory Syndrome, and influenza (Ferris et al 2013;Chesler 2014;Rasmussen et al 2014;Gralinski et al 2015Gralinski et al , 2017Green et al 2017). The CC is an ideal population to study fertility since it contains a large amount of genetic diversity, has wide variation in fertility, and has complementary resources to validate discoveries (Threadgill and Churchill 2012;Morgan and Welsh 2015;Morgan et al 2017).…”

Back to the Future: Multiparent Populations Provide the Key to Unlocking the Genetic Basis of Complex Traits

“…Gralinski et al 2017) and West Nile(Green et al 2017) virus infections to those associated with fertility(Shorter et al 2017) allergensKelada (2016) Morgan et al (2016). andDumont et al (2017) also provide insights into genome structure.…”

Mouse Models as Resources for Studying Infectious Diseases

“…75,79 (D) Alternatively, investigators can take advantage of the phenotypic variation in the CC to perform genetic mapping studies to identify and study polymorphic host genes associated with variation in infection outcomes. 71,73,74 .…”