Targeting the host immune response during sepsis

尽管抗生素治疗取得了显著进展，但细菌性脓毒症的死亡率仍然高得令人无法接受 和支持性护理。最近的尸检研究清楚地表明，大多数患者表现出 死亡时未解决的脓毒症病灶，表明患者无法有效根除侵入 病原体一个限制突破性战略发展的障碍存在，因为目前的概念和 抗微生物治疗的科学基础仅以细菌为中心，但宿主的机械见解， 病原体之间的相互作用仍然知之甚少。宿主导向策略促进吞噬细胞杀菌 活性和逆转病原体诱导的免疫抑制可能复制癌症的成功 免疫治疗在传染病领域的应用。考虑到这一点，我们已经确定了p120连环蛋白（p120）， 在巨噬细胞中高度表达，在细菌清除中至关重要。这项资助的初步数据表明 脓毒症患者肺泡巨噬细胞中p120的丢失与细菌负荷密切相关 和呼吸功能障碍。p120的特异性巨噬细胞缺失导致细菌性巨噬细胞增殖的显著增加。 盲肠结扎穿孔致小鼠多菌性脓毒症时肺和肝脓肿的负荷。 重要的是，人肺泡巨噬细胞和小鼠骨髓源性巨噬细胞中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，骨髓的孵化- 含细菌的衍生巨噬细胞诱导p120快速类小泛素化和非类小泛素化p120的表达 p120缺失的小鼠骨髓源性巨噬细胞中的突变体完全阻止E. 杆菌这些有趣的发现支持了巨噬细胞中p120的表达是巨噬细胞的重要功能的假设。 细菌感染根除的决定因素，因此败血症的结果。我们将检验这一假设 目的：1）探讨巨噬细胞p120在细菌清除和肺损伤中的作用 脓毒症期间的损伤。2)阐明p120控制细菌清除的分子机制。第三章 探讨靶向巨噬细胞p120对脓毒性损伤的治疗潜力。这项建议 将破译一种以前未被认识的控制宿主和细菌病原体相互作用的机制。 这些研究的完成将促进新型免疫增强治疗药物的开发 改善细菌性脓毒症治疗的临床结果和生存率的策略。

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.