Role of Type 2 Immunity in Innate Protection from C. difficile

2 型免疫在艰难梭菌先天保护中的作用

• 批准号: 10467414
• 负责人: William A Petri
• 金额: $ 56.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-02 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467414
• 关键词: Acute; Adoptive Transfer; Amphiregulin; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bioinformatics; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Church; Clostridium difficile; Effector Cell; Epidemic; Epithelial; Flow Cytometry; Foundations; Goblet Cells; Human; Human Resources; Immune; Immune system; Immunity; Immunotherapy; Individual; Infection; Inflammation; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Intervention Studies; Intestines; Knowledge; Lymphoid Cell; Mediating; Modeling; Mucous body substance; Mus; Natural Immunity; North America; Nosocomial Infections; Phenotype; Process; Production; Relapse; Research; Research Personnel; Resolution; Role; Signal Transduction; Systems Biology; TLR2 gene; Testing; Time; Toxin; Transferase; Virulence; Walking; Weight Gain; arginase; cell type; commensal microbes; conditional knockout; cytokine; dysbiosis; eosinophil; experimental study; fecal transplantation; gastrointestinal epithelium; gut microbiota; healing; innovation; intestinal epithelium; macrophage; macrophage product; microbiota; mouse model; prevent; professional atmosphere; receptor; response; single-cell RNA sequencing; transcriptomics

Project Summary Hypothesis: Type 2 innate immunity protects the gut from C. difficile infection (CDI) via the coordinated actions of innate lymphoid cell type 2 (ILC2), eosinophils and alternatively-activated macrophages (AAM). Progress: The first 5 years of support from 5R01AI124214 demonstrated that microbiota-elicited type 2 immunity protects from CDI. It does so at two stages, protecting the epithelial barrier during acute CDI, and promoting healing. We discovered that key steps in this process are: (i) IL-25 and IL-33 production by the intestine in response to commensal microbes; (ii) IL-25 and IL-33 activation of ILC2; and (iii) protection by downstream type 2 cellular effectors eosinophils and AAM. The key knowledge gap is how ILC2, eosinophils and AAM act to protect. Significance: C. difficile is a CDC “Urgent Antibiotic Resistance Threat” as the number one hospital-acquired infection in North America. Current therapy with antibiotics is inadequate, as relapse occurs in up to 20% and death in 6%. The proposed studies, by identifying how innate immunity protects, offer the promise of immunotherapy as an addition to current approaches to treatment and as a replacement for fecal transplant. Investigators: The PI William Petri discovered the role of type 2 immunity in CDI in the prior 5 year period of support. Key personnel include Maureen Carey (systems biology), Stacey Burgess (spectral flow cytometry), Katia Sol-Church (scRNAseq) and Jennie Ma and Pankag Kumar (bioinformatics). Innovative aspects are foremost the hypothesis that type 2 innate immunity protects from C. difficile and that the immune system can be harnessed to treat CDI. Approach: We will describe during the course of CDI the individual and collective mechanisms by which ILC2 (Aim 1), eosinophils (Aim 2) and AAM (Aim 3) respond to CDI in the murine model. We will identify common underlying mechanisms of protection by the coordinated action of these 3 cell effectors of type 2 innate immunity. The studies will include single cell transcriptomics (scRNAseq) in the presence or absence of protective upstream activation by the intestinal epithelial cytokines IL-25 and IL-33, and interventional studies to directly test the contributions of innate immune effector cells on protection. The environment for the work is highly interactive with all of the key personnel located within a few minutes walk of Dr. Petri’s C. difficile research lab. Successful completion of these studies will identify the mechanisms by which cellular type 2 responses protect from CDI and lay the foundation for immunotherapy for CDI as an adjunct to antibiotics and as a replacement for fecal microbiota transplant (FMT).

项目概要 假设：2 型先天免疫通过协调保护肠道免受艰难梭菌感染 (CDI) 先天淋巴细胞 2 型 (ILC2)、嗜酸性粒细胞和替代激活巨噬细胞 (AAM) 的作用。 进展：5R01AI124214 的前 5 年支持表明微生物群引发了 2 型 免疫可以通过两个阶段来保护 CDI，即在急性 CDI 期间保护上皮屏障，以及 我们发现该过程中的关键步骤是： (i) IL-25 和 IL-33 的产生。 肠道对共生微生物的反应；(ii) IL-25 和 IL-33 激活 ILC2； 下游 2 型细胞效应器嗜酸性粒细胞和 AAM 关键的知识差距是 ILC2、嗜酸性粒细胞如何发挥作用。 AAM 采取行动进行保护。 意义：艰难梭菌是 CDC 的“紧急抗生素耐药性威胁”，是医院获得性排名第一的细菌 目前的抗生素治疗在北美是不够的，高达 20% 的患者会出现复发。 拟议的研究通过确定先天免疫如何提供保护，有望降低 6% 的死亡率。 免疫疗法作为当前治疗方法的补充并替代粪便移植。 调查人员：PI William Petri 在过去 5 年中发现了 2 型免疫在 CDI 中的作用 主要人员包括 Maureen Carey（系统生物学）、Stacey Burgess（光谱流式细胞术）、 Katia Sol-Church (scRNAseq) 以及 Jennie Ma 和 Pankag Kumar（生物信息学）。 创新方面最重要的是这样的假设：2 型先天免疫可以预防艰难梭菌，并且 可以利用免疫系统来治疗 CDI。 方法：我们将在 CDI 过程中描述 ILC2 所采用的个人和集体机制 （目标 1）、嗜酸性粒细胞（目标 2）和 AAM（目标 3）在小鼠模型中对 CDI 做出反应。 这 3 个 2 型先天细胞效应器协调作用的潜在保护机制 这些研究将包括存在或不存在的情况下的单细胞转录组学（scRNAseq）。 肠上皮细胞因子 IL-25 和 IL-33 的保护性上游激活以及介入研究 直接测试先天免疫效应细胞对保护的贡献。 工作环境与所有关键人员在几分钟内就位高度互动 佩特里博士的艰难梭菌研究实验室的步道。 成功完成这些研究将确定 2 型细胞反应的机制 预防 CDI 并为 CDI 免疫治疗奠定基础，作为抗生素的辅助药物和治疗药物 粪便微生物移植（FMT）的替代品。