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.

项目总结/文摘