Forward Genetic Analysis of type I interferon responses to cytosolic nucleotides

描述（由申请人提供）：本研究的目的是利用MOLF/EiJ和C57 BL/6小鼠之间的遗传差异，以发现改变对细胞内病毒和细菌感染的免疫应答的新基因或多态性等位基因。了解等位基因遗传对免疫反应的影响对于了解遗传多样性人群中疾病易感性的差异至关重要。使用正向遗传学，我们发现了多个基因座与这两个小鼠亚种之间的细胞因子反应差异相关。一个基因座含有一个自然发生的功能丧失Tmem 173等位基因在MOLF/EiJ小鼠，赋予缺乏干扰素反应的胞质DNA和c-di-AMP。在目标1中，我对这些新的多态性如何消除干扰素信号的研究将导致对这种信号通路如何工作的更深入的理解。此外，在目的2中，这些小鼠将用于产生活感染模型，以将人功能丧失等位基因（HAQ）在对由细胞内病原体如单核细胞增生李斯特菌、结核分枝杆菌和疱疹病毒引起的疾病的易感性中的重要性联系起来。在这项研究中，其他基因座已被发现有助于这种差异免疫反应的MOLF/EiJ小鼠细胞质DNA和c-di-AMP。在我的项目中，在目标1中提出了进一步的映射，可以发现在细胞介导的免疫中重要的新基因。

DESCRIPTION (provided by applicant): The goal of this study is to exploit the genetic variance between MOLF/EiJ and C57BL/6 mice to discover novel genes or polymorphic alleles that modify immune responses to intracellular viral and bacterial infections. Understanding the influence of allelic inheritance on immune responses is essential to understanding differences in susceptibility to disease in the genetically diverse human population. Using forward genetics we have found multiple loci linked with differences in cytokine responses between these two murine sub species. One locus contained a naturally occurring loss-of-function Tmem173 allele in MOLF/EiJ mice that confers a lack of interferon response to cytosolic DNA and c-di-AMP. In Aim 1, my investigation into how these novel polymorphisms abrogate interferon signaling will lead to a deeper understanding of how this signaling pathway works. Furthermore, these mice will be used to generate a live infection model, in Aim 2, to relate the importance of the human loss-of-function allele (HAQ) in susceptibility to diseases caused by intracellular pathogens such as Listeria Monocytogenes, Mycobacterium tuberculosis, and Herpes viruses. In this study, other loci have been found to contribute to this differential immune response of MOLF/EiJ mice to cytosolic DNA and c-di-AMP. Further mapping proposed in my project, in Aim 1, can lead to the discovery of novel genes important in cellular-mediated immunity.