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.

项目摘要 激活的髓样细胞促进宿主对感染的抗性，但也会驱动可能损害的感染 组织并导致慢性疾病。那就是，免疫系统必须仔细平衡反应 调节髓样细胞的积累和激活 - 理想地优化了针对感染性的受保护反应 代理同时限制炎症反应。我们相信对髓样细胞的理解有了改进的了解 调节活动将有助于开发更具体地靶向超过炎症的疗法 同时保留受保护的抗微生物髓样细胞活性。该建议专门针对 I型IFN抑制髓样细胞反应的机制，并解决了这种抑制是否抑制 DP16小鼠的鼠模型中的宿主易感性提高。 I型干扰素（IFN）会影响保护病毒的抗病毒状态，但这些细胞因子也 具有免疫调节功能，在临床环境中用于治疗炎症相关疾病。 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 实验室和其他人以前已经证明了I型IFNS的这些“促细菌”效应与 髓样细胞抗微生物激活的阻尼。在这里，我们研究了I型IFN和 在染色体的背景下，髓样细胞中的IFNGR1降低了髓样细胞的抗性/敏感性 小鼠在人类中模仿21的三体性。这些努力的结果可能会推动主机指导 疗法应对IFNGR1沉默的疗法来增强DS和严重患者的免疫反应 细菌感染，包括对常规抗生素抗性的病原体感染。