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Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.

定义微生物群衍生的环状二核苷酸在启动抗病毒免疫防御中的作用。

基本信息

批准号：
10326823
负责人：
Sara Cherry
金额：
$ 40.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326823
关键词：
Ablation Address Age Aging Anabolism Animal Model Animals Apical Autophagocytosis Bacillus subtilis Bacteria Binding Biochemical Biological Assay Bypass Cells Complement Coupled Cytoplasm Data Development Dinucleoside Phosphates Disease Drosophila genus Enteral Enterocytes Epithelial Epithelial Cells Gastrointestinal tract structure Gene Deletion Genes Genetic Models Genetic study Homeostasis Human Immune Immunity Immunologics Infection Infection Control Intestines Knowledge Ligands Longevity Maintenance Modeling Molecular Nucleotides Oral Organism Pathogenesis Pathway interactions Pattern Pattern recognition receptor Periodicity Permeability Play Predisposition Probiotics Refractory Role Shapes Structure TBK1 gene Therapeutic Vertebrates Virus Virus Diseases antiviral immunity bacterial community body cavity commensal bacteria cost deletion library dysbiosis enteric infection enteric pathogen enteric virus infection feeding fly gene product gut microbiota insight intestinal barrier intestinal epithelium juvenile animal microbial microbiome microbiota mutant novel strategies novel therapeutic intervention pathogen

项目摘要

Enteric pathogens represent a major group of disease-causing agents, and must overcome the physical and immunological barrier of the gastrointestinal tract. The resident microbiota presents with a large array of ligands and pathogen-associated molecular patterns (PAMPs) which can prime immune defenses, through pattern recognition receptors (PRRs), both on enterocytes and immune resident cells. Indeed, microbial-derived TLR ligands are necessary for the development and maintenance of the intestinal barrier and immune homeostasis. Moreover, the microbiota is not static and imbalanced bacterial communities, termed dysbiosis, impact immunity, in particular during aging. Aging is associated with increased susceptibility to enteric pathogens, and how the dysbiotic microbiota alters susceptibility is largely unknown. The complement of microbial-derived ligands that are sensed and that can prime antiviral immunity is incomplete. A better understanding of the molecular mechanisms by which immunity is maintained, how the microbiota and epithelia interact, and how this impacts infection and pathogenesis has the potential to reveal novel strategies to treat enteric viral infections. Studies exploring the role of the microbiota and host genes in the context of aging in enteric infections are challenging in small animal models due to costs and technical hurdles. To overcome our gap in knowledge of the molecular mechanisms that control enteric viral infection, we developed an oral model of infection using the powerful genetic model organism, Drosophila. We found that the gut presents a high barrier to infection: young wild type flies are refractory to oral challenge with human viruses, while inoculation into the body cavity, which bypasses the gut, results in robust infection. The spectrum of antiviral pathways engaged in the gut, and how the microbiota shapes immunity in the intestine is incompletely understood. Preliminarily, we found that Drosophila STING controls infection in the intestine; dSTING mutants are more susceptible to enteric viral infection. STING is known to be activated by cyclic dinucleotides (CDNs). While cGAS can produce CDNs endogenously, STING can also be activated by bacterially derived CDNs. This led us to explore the possibility that commensal bacteria-derived CDNs may impact innate defenses in the gut through STING, as it is known that microbiota-derived CDNs are present in the gut. Our new data identifies a role for microbiota-derived CDNs in antiviral defense. Ablation of the microbiota in young animals leads to increased infection, and feeding these microbiota-deficient flies CDNs was protective. In Aim 1 we will define the role of dSTING in antiviral defense and in Aim 2 we will define the role of commensal-derived CDNs in antiviral defense in young and old animals.

肠道病原体代表了一组主要的致病因子，并且必须克服物理和生物学上的障碍。胃肠道的免疫屏障。常驻微生物群呈现出大量配体和病原体相关分子模式（PAMPs），它们可以通过模式启动免疫防御，识别受体（PRR），在肠细胞和免疫驻留细胞。事实上，微生物来源的TLR 配体对于肠屏障和免疫稳态的形成和维持是必需的。此外，微生物群不是静态和不平衡的细菌群落，称为生态失调，影响免疫力，特别是在老化过程中。衰老与对肠道病原体的易感性增加有关，生态失调的微生物群改变易感性在很大程度上是未知的。微生物衍生配体的补体，可以引发抗病毒免疫的免疫系统是不完整的。更好地理解分子维持免疫力的机制，微生物群和上皮细胞如何相互作用，以及这如何影响感染和发病机制的研究有可能揭示治疗肠道病毒感染的新策略。研究探索肠道感染中微生物群和宿主基因在衰老背景下的作用具有挑战性在小动物模型中，由于成本和技术障碍。为了克服我们在分子学知识上的差距，控制肠道病毒感染的机制，我们开发了一个口服感染模型，使用强大的基因模式生物果蝇我们发现肠道对感染有很高的屏障：年轻的野生型苍蝇对人类病毒的口服攻击是难治的，而接种到体腔中，肠道，导致强烈的感染。参与肠道的抗病毒途径谱，以及微生物群如何肠内免疫力的形成还不完全清楚。初步发现果蝇STING 控制肠道中的感染; dSTING突变体对肠道病毒感染更敏感。STING已知被环状二核苷酸（cyclic dinucleotides，CDN）激活。虽然cGAS可以内源性地产生CDN，但STING也可以由细菌衍生的CDN激活。这使我们探索了肠道细菌来源的 CDN可以通过STING影响肠道中的先天防御，因为已知微生物来源的CDN是存在于肠道中。我们的新数据确定了微生物来源的CDN在抗病毒防御中的作用。消融年轻动物体内的微生物群导致感染增加，喂养这些微生物群缺陷的果蝇CDN 是保护性的在目标1中，我们将定义dSTING在抗病毒防御中的作用，在目标2中，我们将定义共生体衍生的CDN在幼年和老年动物的抗病毒防御中的作用。