Role of IFNs and IFNGR in susceptibility to bacteria in Down syndrome

项目摘要 活化的髓系细胞增强宿主对感染的抵抗力，但也会引发炎症，从而损害 组织，并导致慢性病。因此，免疫系统必须仔细平衡 调节髓系细胞的积聚和激活-理想地优化对感染的保护反应 同时限制炎症反应。我们相信，对髓系细胞如何 调节活动将有助于开发更专门针对过度炎症的治疗方法 同时保留保护性的抗微生物髓系细胞活性。这项提案特别侧重于 I型干扰素抑制髓系细胞反应的机制以及这种抑制是否 在唐氏综合症小鼠模型Dp16小鼠中，有助于增加宿主易感性。 I型干扰素(IFN)诱导一种对病毒具有保护作用的抗病毒状态，但这些细胞因子还 具有免疫调节功能，用于临床治疗炎症相关疾病。 此外，在许多细菌感染中，I型IFN与宿主易感性的增加有关。我们的 Lab和其他人之前已经证明，I型IFN的这些“亲细菌”效应与 抑制髓系细胞抗微生物活性。在这里，我们调查I型IFN的影响和 髓系细胞中IFNGR1在染色体背景下对耐药性/敏感性的下调 小鼠的三倍体，模仿人类的21三体。这些努力的结果可能会推动东道主主导的 对抗Ifngr1沉默的治疗方法增强DS和重症患者的免疫反应 细菌感染，包括对常规抗生素具有抗药性的病原体感染。

Project Summary Activated myeloid cells promote host resistance to infections but also drive inflammation that can damage tissue and contribute to chronic diseases. Thus, the immune system must carefully balance responses that regulate myeloid cell accumulation and activation – ideally optimizing protective responses against infectious agents while limiting inflammatory responses. We believe an improved understanding of how myeloid cell activity is regulated will aid development of therapies that more specifically target excessive inflammation while preserving protective anti-microbial myeloid cell activities. This proposal specifically focuses on a mechanism by which type I IFNs suppress myeloid cell responses and addresses whether such suppression contributes to increased host susceptibility in a murine model for Down syndrome, the Dp16 mouse. Type I interferons (IFNs) induce an antiviral state that is protective against viruses, but these cytokines also have immune regulatory functions and are used in clinical contexts to treat inflammation-associated disease. Further, in a number of bacterial infections type I IFNs are associated with increased host susceptibility. Our lab and others have previously demonstrated that these “pro-bacterial” effects of type I IFNs correlate with dampening of myeloid cell anti-microbial activation. Here, we investigate the impact of type I IFNs and IFNGR1 down regulation in myeloid cells on resistance/susceptibility in the context of a chromosomal triplication in mice that mimics trisomy 21 in humans. Results of these efforts could advance host-directed therapies to counter the silencing of Ifngr1 for boosting immune responses in individuals with DS and severe bacterial infections, including infections by pathogens that are resistant to conventional antibiotics.