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 活化的骨髓细胞促进宿主对感染的抵抗力，但也会导致炎症， 组织，并有助于慢性疾病。因此，免疫系统必须仔细平衡反应， 调节骨髓细胞的积累和激活-理想地优化对感染的保护性反应 药物，同时限制炎症反应。我们相信，进一步了解骨髓细胞 调节活性将有助于开发更特异性针对过度炎症的治疗方法 同时保留保护性抗微生物骨髓细胞活性。该提案特别侧重于一个 I型IFN抑制骨髓细胞应答的机制，并阐明这种抑制是否 在唐氏综合征的鼠模型Dp 16小鼠中， I型干扰素（IFN）诱导抗病毒状态，该抗病毒状态对病毒具有保护作用，但这些细胞因子也 具有免疫调节功能并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与宿主易感性增加相关。我们 实验室和其他人先前已经证明I型IFN的这些“促细菌”作用与以下因素相关： 抑制骨髓细胞抗微生物活化。在这里，我们研究I型干扰素的影响， 骨髓细胞中IFNGR 1下调对染色体背景下耐药/易感性的影响 在小鼠中复制三倍，模拟人类的21三体。这些努力的结果可以促进主机定向 对抗Ifngr 1沉默的疗法，用于增强DS和重度 细菌感染，包括对常规抗生素具有抗性的病原体的感染。