Detection of intestinal pathogens through host surveillance of bacterial toxins

通过宿主细菌毒素监测来检测肠道病原体

• 批准号: 10540312
• 负责人: Samantha Tse
• 金额: $ 3.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540312
• 关键词: Anti-Infective Agents; Anti-Inflammatory Agents; Bacteria; Bacterial Toxins; Bone Marrow Transplantation; Caenorhabditis elegans; Cell Communication; Cells; Cessation of life; Communities; Data; Detection; Development; Embryonic Development; Epithelial Cells; Family; Genes; Genetic Transcription; HNF4A gene; Health; Homologous Gene; Hormone Receptor; Hospitalization; Human; Immune; Immune response; Immunocompromised Host; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Intestines; Ligands; Metabolism; Modeling; Molecular; Monitor; Natural Immunity; Nuclear Hormone Receptors; Nuclear Receptors; Organism; Oxidation-Reduction; Pathogen detection; Pathogenesis; Pathogenicity; Patients; Pattern Recognition; Pattern recognition receptor; Phenazines; Physiological; Positioning Attribute; Process; Protein Isoforms; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Research; Role; Sepsis; Septicemia; Testing; Therapeutic; Toxin; Transcriptional Activation; Transplant Recipients; Virulence; chemotherapy; commensal bacteria; commensal microbes; enteric infection; enteric pathogen; gut colonization; gut inflammation; gut microbiome; human pathogen; immune activation; immunoregulation; insight; interest; intestinal epithelium; model organism; mutant; novel; pathogen; pathogenic bacteria; pathogenic microbe; programs; response; therapeutic target; transcription factor

PROJECT SUMMARY/ABSTRACT Although commensal and pathogenic bacteria can be recognized by host pattern recognition receptors, intestinal epithelial cells target protective inflammatory responses towards pathogenic organisms through mechanisms that are incompletely understood. Additional mechanisms of pathogen sensing must exist that allow intestinal cells to target inflammatory defenses towards bona fide pathogens during an infection, and not harmless commensal bacteria. Pathogenic bacteria can express virulence determinants. Phenazine toxins are a family of redox active virulence determinants that are produced by a variety of human pathogens, including P. aeruginosa. P. aeruginosa can colonize the intestines of immunocompromised patients and cause fulminant septicemia and subsequent death. The mechanism by which intestinal epithelial cells detect P. aeruginosa, and whether this involves the surveillance of phenazine toxins, is not known. Nuclear hormone receptors (NHR) are transcription factors that program adaptive host responses following recognition of specific exogenous or endogenous ligands. In particular, HNF4⍺ is an NHR expressed in the intestine. In the model organism C. elegans, the HNF4⍺ homolog NHR-86 is required for the transcriptional activation of innate immune effector genes that protect against P. aeruginosa infection. The central hypothesis of this proposal is that intestinal epithelial cells detect infection through the surveillance of pathogen-derived phenazine toxins by NHR-86/ HNF4⍺, which directly activates protective anti-pathogen defenses in the intestinal epithelium. The following key preliminary findings support this central hypothesis: i) P. aeruginosa mutants that cannot make phenazine toxins do not activate C. elegans innate immune defenses; ii) synthetic phenazine toxins can activate immune genes; and iii) induction of immune genes by phenazine toxins is dependent on the expression of NHR-86/ HNF4⍺. In this proposal, Aim 1 will characterize the C. elegans immune response towards bacterial phenazine toxins, and Aim 2 will define the role of intestinal NHR-86/HNF4⍺ in detecting P. aeruginosa infection in C. elegans. The research proposed here will define a new concept of immune activation in intestinal epithelial cells and will also attribute a novel role for NHRs in pathogen sensing in the intestine. Insights from these findings may identify unexplored approaches for the development of anti-inflammatory and anti-infective therapies.

项目摘要/摘要 尽管可以通过宿主模式识别受体识别共生和致病细菌，但 肠上皮细胞针对致病生物的受保护的炎症反应通过 未完全理解的机制。必须存在病原体传感的其他机制 允许肠细胞靶向炎症性防御剂在感染过程中，而不是 无害的共生细菌。致病细菌可以表达病毒确定。苯嗪毒素是 由多种人类病原体产生的氧化还原活性病毒决定剂家族，包括P。 铜绿。铜绿假单胞菌可以定居于免疫功能低下的患者的肠子，并引起暴发性 败血症和随后的死亡。肠上皮细胞检测铜绿假单胞菌和 这是否涉及对苯嗪毒素的监测，尚不清楚。核马酮受体（NHR）是 在识别特定外源性或 内源配体。特别是，HNF4⍺是在肠中表达的NHR。在模型生物体中。 秀丽隐杆线虫，HNF4⍺同源性NHR-86是先天免疫效应子的转录激活所必需的 预防铜绿假单胞菌感染的基因。该提议的中心假设是肠道 上皮细胞通过NHR-86/ HNF4⍺直接激活肠上皮中的保护性抗病原体防御。下列 关键初步发现支持此中心假设：i）不能使苯嗪的铜绿假单胞菌突变体 毒素不会激活秀丽隐杆线虫先天免疫防御措施； ii）合成苯丙胺毒素可以激活免疫 基因； iii）苯嗪毒素诱导免疫基因取决于NHR-86/ HNF4⍺。在此提案中，AIM 1将表征秀丽隐杆线虫对细菌苯嗪的免疫冲突 毒素和AIM 2将定义肠NHR-86/HNF4⍺在检测C.铜绿假单胞菌感染中的作用。 秀丽隐杆线。这里提出的研究将定义肠上皮中免疫激活的新概念 细胞，还将归因NHR在肠道中的病原体传感中的新作用。这些见解 调查结果可能会确定抗炎和抗感染的意外方法 疗法。