Targeting the host immune response during sepsis

脓毒症期间针对宿主免疫反应

基本信息

批准号：
10259764
负责人：
Guochang Hu
金额：
$ 58.79万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259764
关键词：
Ablation Actins Alveolar Macrophages Animal Genetics Animal Model Antibiotic Therapy Autopsy Bacteria Bacterial Infections Biological Biology Bone Marrow Cause of Death Cessation of life Clinical Communicable Diseases Complementary DNA Complex Critical Illness Data Development Escherichia coli Future Grant Human Immune Immune response Immunity Immunosuppression In Vitro Infection Control Inflammatory Inflammatory Response Injury Invaded Knowledge Liposomes Liver Abscess Lung Lung Abscess Mediating Mind Molecular Mus Neutrophil Infiltration Outcome Pathway interactions Patients Phagocytes Phagocytosis Population Respiration Disorders Role Safety Sepsis Series Signal Transduction Sumoylation Pathway Supportive care Testing Therapeutic Treatment Efficacy antimicrobial arrestin 2 bactericide beta-arrestin cancer immunotherapy cecal ligation puncture cofilin cofilin 2 improved in vivo insight lung injury macrophage monocyte mortality mutant novel novel strategies pathogen pathogenic bacteria polymerization polymicrobial sepsis prevent restoration septic septic patients success systemic inflammatory response targeted treatment

项目摘要

Mortality from bacterial sepsis remains unacceptably high despite remarkable advances in antibiotic therapy and supportive care. Recent post-mortem studies have clearly revealed that most patients displayed unresolved septic foci at death, suggesting that patients were unable to effectively eradicate invading pathogens. A barrier limiting breakthrough strategic development exists because the current conceptual and scientific basis for antimicrobial therapy centers solely on the bacterium, yet the mechanistic insight of host- pathogen interaction remains poorly understood. Host-directed strategies to boost phagocyte bactericidal activity and reverse pathogen-induced immunosuppression may replicate the success of cancer immunotherapy in the field of infectious diseases. With this in mind, we have identified p120 catenin (p120), highly expressed in macrophages, to be crucial in bacterial clearance. Preliminary data in this grant indicate that p120 loss in alveolar macrophages obtained from septic patients correlated closely with the bacterial loads and respiratory dysfunction. Specific macrophage deletion of p120 resulted in dramatic increase in bacterial load in the lung and liver abscess in polymicrobial sepsis induced by cecal ligation and puncture in mice. Importantly, depletion of p120 in human alveolar macrophages and murine bone marrow-derived macrophages nearly completely blocked phagocytosis of bacteria. Further study revealed that incubation of bone marrow- derived macrophages with bacteria induced rapid p120 sumoylation and expression of non-sumoylatable p120 mutant in p120-depleted mouse bone marrow-derived macrophages completely prevented phagocytosis of E. coli. These intriguing findings support the hypothesis that p120 expression in macrophages is an important determinant of eradication of bacterial infections and therefore outcome of sepsis. We will test this hypothesis via the following specific aims: 1) To evaluate the role of macrophage p120 in bacterial clearance and lung injury during sepsis. 2) To elucidate the molecular mechanisms by which p120 controls bacterial clearance. 3) To examine the therapeutic potential of targeting macrophage p120 for treatment of septic injury. This proposal will decipher a previously unrecognized mechanism controlling the interaction of host and bacterial pathogens. The completion of the proposed studies will promote the development of novel immune-enhancing therapeutic strategies to improve clinical outcomes and survival for the treatment of bacterial sepsis.

尽管抗生素疗法取得了显着进步，但细菌败血症的死亡率仍然不可接受和支持性护理。最近的验尸研究清楚地表明，大多数患者显示死亡时未解决的化粪池灶，表明患者无法有效地消除入侵病原体。限制突破战略发展的障碍是因为当前的概念和抗菌治疗的科学基础仅在细菌上，但宿主的机理见解 - 病原体的相互作用知之甚少。宿主指导的策略来增强吞噬细胞杀菌活性和反向病原体诱导的免疫抑制可能会复制癌症的成功传染病领域的免疫疗法。考虑到这一点，我们已经确定了P120 Catenin（P120），在巨噬细胞中高度表达，对于细菌清除至关重要。该赠款中的初步数据表明从化粪池患者获得的肺泡巨噬细胞中的P120损失与细菌载荷紧密相关和呼吸功能障碍。 p120的特定巨噬细胞缺失导致细菌急剧增加在小鼠的盲肠和穿刺诱导的多因素败血症中，肺和肝脓肿的负荷。重要的是，人类肺泡巨噬细胞和鼠骨髓衍生的巨噬细胞中P120的耗竭几乎完全阻断了细菌的吞噬作用。进一步的研究表明，骨髓的孵育细菌衍生的巨噬细胞诱导的p120 sumoylation and dobybatable P120的表达 P120缺失的小鼠骨髓来源的巨噬细胞中的突变体完全阻止了E。大肠杆菌。这些有趣的发现支持以下假设：巨噬细胞中的p120表达是一个重要的消除细菌感染的决定因素，因此是败血症的结果。我们将检验这个假设通过以下特定目的：1）评估巨噬细胞p120在细菌清除和肺中的作用败血症期间受伤。 2）阐明p120控制细菌清除率的分子机制。 3）检查靶向巨噬细胞P120治疗败血性损伤的治疗潜力。这个建议将破译一种先前无法识别的机制，该机制控制了宿主和细菌病原体的相互作用。拟议研究的完成将促进新型免疫增强治疗的发展改善细菌败血症治疗临床结果和生存的策略。