Diabetes and Inflammation During Infection

感染期间的糖尿病和炎症

• 批准号: 9223117
• 负责人: BRAD J SPELLBERG
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223117
• 关键词: Acinetobacter baumannii; Advanced Glycosylation End Products; Agonist; American; Antibiotic Resistance; Antibiotics; Aphorisms; Automobile Driving; Binding; Biological Markers; Businesses; Cell physiology; Centenarian; Clinical; Clinical Data; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Ensure; Escherichia coli; Future; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Grant; Healthcare; Hyperglycemia; Immune; Immune response; Immunity; Immunosuppression; Immunotherapy; Infection; Inflammation; Inflammatory; Insulin; Iron; Klebsiella pneumonia bacterium; Knockout Mice; Lead; Leukocytes; Lung; Mediating; Metabolic; Methods; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Mycoses; Natural Immunity; Obesity; Outcome; Output; Pathway interactions; Patients; Pharmacologic Substance; Placebos; Predisposition; Residual state; Role; Sepsis; Signal Pathway; Signal Transduction; Streptozocin; TLR4 gene; Translating; Translations; Wild Type Mouse; Work; bacterial resistance; diabetic; diabetic patient; immunoregulation; improved outcome; inhibitor/antagonist; innovation; mortality; non-diabetic; novel; receptor; resistant strain; response; small molecule; small molecule therapeutics; synergism; translational approach; translational impact

PROJECT SUMMARY/ABSTRACT For more than 100 years, diabetes has been considered an immune-suppressed condition. In contrast, we hypothesize that the opposite is true: worse outcomes of Gram-negative infection in diabetics are due to diabetes-driven enhanced immunity because: 1) Toll-like receptor 4 (TLR4) is anti-protective during infection caused by Gram negative bacteria; 2) TLR4 inflammatory output in response to LPS is exacerbated in diabetics; 3) we recently found that blocking the binding of Advanced Glycation Endproducts (AGE) to their receptor (RAGE) ameliorated hyper-susceptibility of diabetic mice to Gram-negative infection; and 4) both TLR4 and RAGE can signal via MyD88, suggesting a mechanism for RAGE/TLR4 synergy. Our central premise—diabetes enhances rather than suppresses the innate response to infection—has novel translational impact. Specifically, immunomodulation to improve outcomes of infection in diabetic hosts should seek to reverse a 100 year-old maxim: suppress the innate response rather than enhance it. We seek to: 1) determine the RAGE/TLR4 signaling relationships during I.V. and lung infections caused by Gram-negative bacteria; and 2) develop translational solutions using promising compounds to normalize immune responses, reducing morbidity and mortality. Our Aims are to: Specific Aim 1: Define the role of MyD88- vs. TRIF-signaling during I.V. and lung infection in diabetic mice. HYPOTHESIS: MyD88 is the signaling pathway mediating susceptibility to Gram-negative infection in diabetic mice, since it can independently signal for TLR4 and RAGE, creating potential for synergistic inflamm- ation. Methods: MyD88 and TRIF are the primary pathways responsible for TLR4 signaling. We found that TLR4 disruption markedly but incompletely protected diabetic mice from A. baumannii infection, possibly because of residual signaling via MyD88 by RAGE. To define the pathway driving outcome, will compare survival, sepsis biomarkers, and bacterial burden during I.V. and lung infection in wild type (pos. control) vs. TLR4-KO (neg. control), MyD88-KO, and TRIF-KO mice that are diabetic or treated with a RAGE-agonist. Specific Aim 2: Determine the potential for a combination of inhibitors presently in pharmaceutical development against TLR4 and RAGE to alter outcomes during Gram-negative bacterial infection in diabetic hosts. HYPOTHESIS: Simultaneous inhibition of TLR4 and RAGE will provide superior outcomes from infection. Methods: We will compare survival, sepsis biomarkers, and bacterial burden in non-diabetic (neg. control) vs. diabetic mice infected I.V. or through the lungs, and treated with placebo (pos. control) vs. 1) a TLR4 antagonist; 2) a RAGE antagonist; or 3) combination of both. To ensure generalizability, mice will be infected with three antibiotic-resistant bacteria: A. baumannii, E. coli, and Klebsiella pneumoniae. IMPACT: These results will enable translation of immune therapies for these deadly infections, and will enable an R01 to define downstream RAGE signaling and metabolic mechanisms driving inflammation in diabetes.

项目概要/摘要 一百多年来，糖尿病一直被认为是一种免疫抑制疾病。相比之下，我们 假设相反的情况是正确的：糖尿病患者革兰氏阴性菌感染的更糟糕结果是由于 糖尿病驱动的免疫力增强，因为：1) Toll 样受体 4 (TLR4) 在感染期间具有抗保护作用 由革兰氏阴性菌引起； 2）TLR4响应LPS的炎症输出在以下情况下加剧： 糖尿病患者； 3) 我们最近发现，阻断高级糖基化终产物 (AGE) 与其结合 受体（RAGE）改善糖尿病小鼠对革兰氏阴性菌感染的过度敏感性； 4) 两者 TLR4 和 RAGE 可以通过 MyD88 发出信号，这表明 RAGE/TLR4 协同作用的机制。 我们的中心前提是糖尿病增强而不是抑制对身体的固有反应 感染——具有新颖的转化影响。具体来说，免疫调节可以改善结果 糖尿病宿主的感染应该扭转一百年前的格言：抑制先天反应 而不是增强它。我们寻求：1）确定 I.V. 期间 RAGE/TLR4 信号传导关系。和肺 革兰氏阴性菌引起的感染； 2）利用有前景的技术开发转化解决方案 化合物使免疫反应正常化，降低发病率和死亡率。我们的目标是： 具体目标 1：定义 MyD88 与 TRIF 信号传导在 I.V. 过程中的作用。和糖尿病患者的肺部感染 老鼠。假设：MyD88 是介导革兰氏阴性菌感染易感性的信号通路 糖尿病小鼠，因为它可以独立发出 TLR4 和 RAGE 信号，创造协同炎症的潜力 化。方法：MyD88 和 TRIF 是负责 TLR4 信号传导的主要途径。我们发现 TLR4 破坏显着但不完全地保护糖尿病小鼠免受鲍曼不动杆菌感染，可能 因为 RAGE 通过 MyD88 残留信号。为了定义驱动结果的途径，将比较 静脉注射期间的存活率、脓毒症生物标志物和细菌负荷野生型（对照）与野生型的肺部感染 患有糖尿病或接受 RAGE 激动剂治疗的 TLR4-KO（阴性对照）、MyD88-KO 和 TRIF-KO 小鼠。 具体目标 2：确定目前药物中抑制剂组合的潜力 针对 TLR4 和 RAGE 的开发可改变革兰氏阴性细菌感染期间的结果 糖尿病宿主。假设：同时抑制 TLR4 和 RAGE 将提供更好的结果 免受感染。方法：我们将比较非糖尿病患者的生存率、败血症生物标志物和细菌负荷 （阴性对照）与静脉注射感染的糖尿病小鼠相比或通过肺部，并用安慰剂治疗（对照组）与 1) TLR4拮抗剂； 2) RAGE拮抗剂；或 3) 两者的组合。为了确保普遍性，小鼠将 感染三种抗生素耐药细菌：鲍曼不动杆菌、大肠杆菌和肺炎克雷伯菌。 影响：这些结果将使针对这些致命感染的免疫疗法得以转化，并将使 R01 定义驱动糖尿病炎症的下游 RAGE 信号传导和代谢机制。