Forward Genetic Analysis of type I interferon responses to cytosolic nucleotides

描述(申请人提供)：这项研究的目标是利用Molf/EIJ和C57BL/6小鼠之间的遗传差异来发现改变细胞内病毒和细菌感染的免疫反应的新基因或多态等位基因。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的人类群体中疾病易感性的差异是至关重要的。利用正向遗传学，我们发现了与这两个小鼠亚种之间的细胞因子反应差异有关的多个基因座。在Molf/EIJ小鼠中，一个基因座包含一个自然发生的功能丧失的Tem173等位基因，该基因导致对胞浆DNA和c-diAMP缺乏干扰素反应。在目标1中，我对这些新的多态如何消除干扰素信号的研究将导致对这一信号通路如何工作的更深层次的理解。此外，在目标2中，这些小鼠将被用来产生活体感染模型，以说明人类功能丧失等位基因(HAQ)在由单核细胞增多性李斯特菌、结核分枝杆菌和疱疹病毒等细胞内病原体引起的疾病易感性中的重要性。在本研究中，已发现其他基因座有助于Molf/EIJ小鼠对胞质DNA和c-diAMP的这种差异免疫反应。我在目标1的项目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.