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C57BL/6小鼠之间的遗传变异，发现改变细胞内病毒和细菌感染免疫反应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理解不同基因人群对疾病易感性的差异至关重要。利用正向遗传学，我们发现了与这两个小鼠亚种之间细胞因子反应差异相关的多个位点。在MOLF/EiJ小鼠中，一个基因座包含一个自然发生的功能缺失的Tmem173等位基因，导致对细胞质DNA和c-di-AMP缺乏干扰素应答。在Aim 1中，我对这些新的多态性如何消除干扰素信号传导的调查将导致对这种信号传导途径如何工作的更深层次的理解。此外，在Aim 2中，这些小鼠将用于生成活感染模型，以联系人类功能丧失等位基因（HAQ）在细胞内病原体（如单核细胞增生李斯特菌、结核分枝杆菌和疱疹病毒）引起的疾病易感性中的重要性。在这项研究中，发现了其他基因座有助于MOLF/EiJ小鼠对胞质DNA和c-di-AMP的差异免疫反应。在我的项目中，在Aim 1中提出的进一步定位可以导致发现在细胞介导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.