In vivo mechanisms of Mycobacterium tuberculosis control and susceptibility

结核分枝杆菌控制和易感性的体内机制

• 批准号: 10612348
• 负责人: Dmitri I Kotov
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612348
• 关键词: Anti-Bacterial Agents; Antibiotic Therapy; Autoimmune Diseases; Bacteria; Biological Response Modifiers; Bone Marrow; Cause of Death; Cells; Cessation of life; Chimera organism; Chronic; Clinical Trials; Communication; Cytoprotection; Data; Data Set; Development; Disease; Environment; Gene Expression; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Health; Hematopoietic; Heterogeneity; Host Defense; Human; IL18 gene; IL1R2 gene; Immune; Immune response; Immunologic Factors; Immunosuppression; Incidence; Individual; Infection; Infection Control; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Knowledge; Laboratories; Lung; Macrophage; Mediating; Mouse Strains; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Neutrophilia; Pathway interactions; Population; Predisposition; Production; Productivity; Research Design; Role; Series; Signal Transduction; T cell response; TNF gene; Testing; Therapeutic; Time; Tuberculosis; Vaccines; acute infection; anakinra; antagonist; candidate identification; cytokine; enhancing factor; experimental study; in vivo; in vivo evaluation; inflammatory milieu; inhibitor; insight; interleukin-22; mortality; neutrophil; novel; novel strategies; pathogen; programmed cell death protein 1; protective effect; protective factors; receptor; resistant strain; response; restraint; sensor; single-cell RNA sequencing; success; vaccine efficacy; vaccine strategy

Project Summary Mycobacterium tuberculosis (Mtb) infects the lungs causing 1.6 million deaths a year. The only vaccine approved for tuberculosis has limited efficacy. Additionally, antibiotic treatment requires six months, but can require two or more years for multi-drug resistant strains that are becoming more prevalent. Therefore, development of a host-directed therapeutic strategy that directly targets the Mtb reservoir would dramatically impact human health. I propose to identify novel innate immune factors that protect against Mtb infection in vivo, which could be the basis of such a therapeutic approach. Specific Aims: During Mtb infection, inflammatory cytokines like IL-1 stimulate non-infected cells to produce factors that enhance anti-bacterial activity of Mtb-bearing cells. While IL-1 is critical for protection against Mtb, its mechanism of action is unknown. Aim 1) We have identified IL-1 sensing cells in Mtb-infected lungs and IL-1-induced genes expressed by these cells. I will test whether natural killer T 17 cells, one of the IL-1 sensing populations, provides protection against Mtb. Additionally, I will determine which IL-1-induced genes act directly on Mtb infected macrophages in vivo to confer the protective effect of IL-1. Aim 2) Neutrophils are detrimental in Mtb- susceptible mouse strains and neutrophilia positively correlates with bacterial burden and mortality in humans. However, it is unclear how neutrophils interfere with the host response to Mtb. We have previously shown that IL-1 receptor antagonist (IL-1Ra) is an immunosuppressive molecule that limits Mtb control in a susceptible mouse strain. As IL-1Ra is highly expressed by neutrophils, I will determine whether neutrophils inhibit the protective response against Mtb through their production of IL-1Ra and whether this immunosuppressive function is conserved across multiple Mtb susceptible strains. Additionally, I will determine whether neutrophils exploit other immunosuppressive pathways, like IL-18 signaling inhibition and PD-1, to hinder the productive immune response to Mtb. Study Design: I will define how communication between non-infected and infected cells leads to control of tuberculosis infection by generating mixed bone marrow chimeras. These experiments will test the in vivo relevance of IL-1-driven gene expression for candidates identified in our single cell RNA- sequencing dataset of Mtb-infected lungs. Additionally, I will leverage our single cell RNA-sequencing dataset to determine how neutrophils inhibit control of the infection in Mtb-sensitive mouse strains. Potential Impact: The identification of protective and inhibitory regulators of Mtb control can serve as the basis for host-directed therapies to treat Mtb infection, which will be a major advance for the field.

项目摘要 结核分枝杆菌（MTB）感染每年160万人死亡的肺部。唯一的疫苗 批准结核病的功效有限。此外，抗生素治疗需要六个月，但可以 需要两年或更长时间的多药耐药菌株，这些菌株变得越来越普遍。所以， 开发直接针对MTB储层的宿主定向的治疗策略将极大地针对 影响人类健康。我建议确定可防止MTB感染的新型先天免疫因子 体内，这可能是这种治疗方法的基础。具体目的：MTB感染期间， IL-1（IL-1）炎症细胞因子刺激未感染的细胞产生增强抗细菌的因素 含MTB细胞的活性。尽管IL-1对于保护MTB至关重要，但其作用机理是 未知。 AIM 1）我们已经鉴定了MTB感染的肺和IL-1诱导的基因中的IL-1传感细胞 由这些细胞表达。我将测试自然杀手t 17个细胞（IL-1传感人群之一）是否是 提供针对MTB的保护。此外，我将确定直接在MTB上起作用哪些IL-1诱导的基因 体内感染巨噬细胞以赋予IL-1的保护作用。目标2）中性粒细胞在MTB- 易感小鼠菌株和中性粒细胞与人类的细菌负担和死亡率正相关。 但是，尚不清楚中性粒细胞如何干扰宿主对MTB的反应。我们以前已经表明 IL-1受体拮抗剂（IL-1RA）是一种免疫抑制分子，可限制易感的MTB对照 小鼠应变。由于IL-1RA由中性粒细胞高度表达，因此我将确定中性粒细胞是否抑制 通过生产IL-1RA以及该免疫抑制，对MTB的保护反应 功能在多个MTB易感性菌株中保存。另外，我将确定中性粒细胞是否 利用其他免疫抑制途径，例如IL-18信号抑制和PD-1，以阻碍生产力 对MTB的免疫反应。研究设计：我将定义未感染和感染之间的沟通方式 细胞通过产生混合骨髓嵌合体控制结核病感染。这些实验 将测试IL-1驱动的基因表达与我们的单细胞RNA-鉴定的候选物的体内相关性 MTB感染肺的测序数据集。此外，我将利用我们的单细胞RNA序列数据集 确定中性粒细胞如何抑制对MTB敏感小鼠菌株感染的控制。潜在影响： MTB控制的保护性和抑制性调节剂的识别可以作为宿主指导的基础 治疗MTB感染的疗法，这将是该领域的重大进步。