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A. Actinomycetemcomitans Cdt Induces Pro-Inflammatory Innate Immune Responses

A.放线菌 Cdt 诱导促炎症先天免疫反应

基本信息

批准号：
10438935
负责人：
Kathleen Boesze-Battaglia
金额：
$ 51.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10438935
关键词：
Actinobacillus actinomycetemcomitans Antigens Apoptosis Apoptotic Arachidonic Acids Binding Carrier Proteins Caspase Cell Cycle Arrest Cell Line Cell physiology Cells Cessation of life Cholesterol Chronic Complex Defect Dinoprostone Disease Eicosanoids Endosomes Epithelial Cells Event Exhibits Goals Heat shock proteins Heat-Shock Proteins 90 Host Defense Human Immunotoxins Impairment Individual Infection Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inflammatory Response Pathway Innate Immune Response Interleukin-18 Interleukin-6 Intoxication Investigation Knowledge Link Lipids Lymphocyte Lysosomes Lytic Mediating Membrane Lipids Membrane Microdomains Microbe Molecular Movement Organism Outcome PI3 gene Pathogenesis Pathogenicity Pathway interactions Periodontal Diseases Periodontitis Phagocytes Phagocytosis Phagolysosome Phagosomes Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Play Production Proliferating Property Prostaglandin-Endoperoxide Synthase Proteins Research Role Signal Pathway Signal Transduction Sorting - Cell Movement System Targeted Toxins Testing Therapeutic Intervention Thromboxanes Toxic effect Toxin Translating Virulence Factors adaptive immune response cell type cellugyrin cytokine cytolethal distending toxin holotoxins insight macrophage microbial monocyte novel oral pathogen pathogen repaired response retrograde transport small molecule spatiotemporal synaptogyrin trafficking tripolyphosphate vesicle transport virtual

项目摘要

Periodontal disease is a chronic inflammatory disorder driven by polymicrobial infection. The pathogenesis of this disorder involves activation, and possibly perturbation, of both innate and adaptive immune responses. Over the course of our investigation we have demonstrated that Aggregatibacter actinomycetemcomitans (Aa), a putative pathogen implicated in the pathogenesis of localized aggressive periodontitis (LAP), produces an immunotoxin, the cytolethal distending toxin (Cdt). Cdt is a heterotrimeric holotoxin which functions as an AB2 toxin: the cell binding (B) units are comprised of the CdtA and CdtC subunits and the active (A) subunit, CdtB. We have demonstrated that CdtB functions as a 5'-phosphatidylinositol (PI) triphosphate phosphatase as it degrades the PI-3K signaling lipid, PI-3,4,5-triphosphate (PIP3) to PI-3,4P2; this action leads to blockade of the signaling pathway. Blockade of PI-3K signaling in human macrophages leads to a pro-inflammatory cytokine response involving both canonical and noncanonical inflammasome activation. Cdt also induces production of inflammatory mediators derived from arachidonic acid including PGE2 and thromboxanes. Most recently, we have observed phagocytic defects in Cdt-treated macrophages consistent with altered phago-lysosome maturation. We propose that Cdt perturbs macrophage function thereby contributing to both inflammation and sustained infection. Our overarching hypothesis is that the Aa Cdt contributes to altered local host defense which facilitate Aa survival and enables other microbes to evade host defense. The goal of our study is to extend our investigation and advance our knowledge of the molecular events that link PI-3K signaling blockade to downstream pro- inflammatory responses and altered vesicular trafficking and fusion. Specifically, we propose that CdtB induces GSK3â-dependent HSP90 activation and further that HSP90, via its effects on NLRP3, Cox-2 and possibly ESCRT proteins is a critical intermediary in events leading to release of mature cytokines and eicosanoids (specific aim 1). We plan to advance our understanding of the role that Cdt plays activating the noncanonical inflammasome which involve gasdermin D (GSDMD) pore formation and pyroptosis. Our focus will be to determine how CdtB activates caspase-4 and contributes to GSDMD pore formation; the latter studies will focus on PI-3,4P2 and pore repair via the ESCRT system (specific aim2). In specific aim 3 we will focus on perturbation of vesicular transport and phago-lysosome formation. We propose that altered PI distribution due in part to CdtB-mediated production of PI3,4P2 facilitates CdtB retrograde transport and modulates the formation of phago-lysosomes. The long-term goals of our study are to translate our understanding of the molecular events that govern Cdt toxicity and, in turn, the pathogenicity of Cdt-producing organisms. These studies are of particular significance as Cdt is produced not only by Aa but many other pathogens that contribute to chronic infectious and inflammatory disorders. Insight gained through this investigation will advance our understanding of the molecular events underlying LAP and other diseases caused by Cdt-producing organisms and identify new avenues for therapeutic intervention. .

牙周病是一种由多种微生物感染引起的慢性炎症性疾病。的发病机制