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

IFN 和 IFNGR 在唐氏综合症细菌易感性中的作用

• 批准号: 10356944
• 负责人: Laurel L Lenz
• 金额: $ 19.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356944
• 关键词: Address; Agreement; Animal Model; Anti-Inflammatory Agents; Antibiotics; Bacteria; Bacterial Infections; Biological Models; Cell surface; Cells; Chromosome 21; Chronic Disease; Clinical; Development; Disease; Down Syndrome; Down-Regulation; Ensure; Equilibrium; Event; Genes; Genetic Transcription; Half-Life; Host resistance; Human; Human Chromosomes; IFNGR1 gene; Immune; Immune response; Immune system; Impairment; Incidence; Individual; Infection; Infectious Agent; Inflammation; Inflammatory Response; Innate Immune Response; Interferon Type I; Interferon Type II; Interferon-alpha; Interferons; Lead; Ligand Binding; Listeria monocytogenes; Listeriosis; Molecular; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cell Activation; Myeloid Cell Suppression; Myeloid Cells; Orthologous Gene; Pathway interactions; Pneumococcal Infections; Population; Predisposition; Production; Proteins; Publishing; Refractory; Resistance; Resistance to infection; Role; Severity of illness; Signal Transduction; Streptococcus pneumoniae; Surface; Systemic infection; Testing; Therapeutic; Tissues; Transgenes; Transgenic Organisms; Virus; Virus Replication; antimicrobial; bacterial resistance; comorbidity; cytokine; genetic signature; high risk; improved; influenza infection; macrophage; monocyte; mortality risk; mouse model; pathogen; preservation; prevent; promoter; receptor; recruit; response; therapy development

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.

项目概要 激活的骨髓细胞可促进宿主对感染的抵抗力，但也会引起炎症，从而造成损害 因此，免疫系统必须仔细平衡以下反应： 调节骨髓细胞的积累和激活——理想地优化针对感染的保护反应 我们相信，我们对骨髓细胞如何发挥作用有了更深入的了解。 活性受到调节将有助于开发更专门针对过度炎症的疗法 同时保留保护性抗微生物骨髓细胞活性。该提案特别关注于 I 型干扰素抑制骨髓细胞反应的机制，并解决这种抑制是否 有助于增加唐氏综合症小鼠模型（Dp16 小鼠）的宿主易感性。 I 型干扰素 (IFN) 会诱导抗病毒状态，从而抵御病毒，但这些细胞因子也 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 型干扰素与宿主易感性增加有关。 实验室和其他人之前已经证明，I 型干扰素的这些“亲细菌”作用与 在此，我们研究了 I 型干扰素和 I 型干扰素的影响。 骨髓细胞中 IFNGR1 对染色体背景下耐药/易感性的下调 在小鼠中进行三倍体模仿人类 21 三体，这些努力的结果可能会促进宿主导向。 对抗 Ifngr1 沉默的疗法，以增强 DS 和重症患者的免疫反应 细菌感染，包括对传统抗生素有抗药性的病原体感染。