Role of CD14 and other innate immune receptors in severe sepsis

CD14 和其他先天免疫受体在严重脓毒症中的作用

• 批准号: 7559603
• 负责人: Sanna M Goyert
• 金额: $ 38.5万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559603
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult Respiratory Distress Syndrome; Affect; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Biochemistry; Biological Process; Blood; CD14 Antigen; CD14 gene; Cell Adhesion Molecules; Cell surface; Cells; Clinical; Collaborations; Defect; Development; Dose; Encapsulated; Endothelial Cells; Escherichia coli; Event; Exposure to; Failure; Gene Deletion; Goals; Gram-Negative Bacteria; Greater sac of peritoneum; Health; Host Defense; Immune; Immune response; Immunologic Receptors; Immunology; Infection; Infectious Agent; Infiltration; Injection of therapeutic agent; Invaded; Knowledge; Lead; Life; MAP Kinase Gene; MAPK14 gene; Measures; Mediator of activation protein; Microbiology; Molecular; Molecular Biology; Morbidity - disease rate; Multiple Organ Failure; Mus; Neutrophil Infiltration; Organ failure; Organism; Outcome; Pathway interactions; Patients; Peritoneal Fluid; Phagocytosis; Play; Process; Production; Reagent; Recruitment Activity; Regulation; Resistance; Resistance to infection; Role; Sepsis; Sepsis Syndrome; Septic Shock; Serum; Signal Pathway; Signaling Molecule; Site; TLR4 gene; TNF gene; Testing; Tissues; Toll-Like Receptor 2; bacterial resistance; base; capsule; chemokine; clinically significant; cytokine; experience; insight; killings; microorganism; migration; mortality; mouse model; mutant; neutrophil; novel; prevent; public health relevance; receptor; research study; response; tool

DESCRIPTION (provided by applicant): Sepsis, characterized by a systemic bacterial infection and systemic inflammatory response syndrome (SIRS), can lead to life-threatening conditions including multi-organ failure and septic shock. It has become increasingly apparent that the ability to effectively clear microorganisms may be one of the most important factors in preventing morbidity and mortality due to sepsis and septic shock. Neutrophils (PMN) play an essential role in this process. In response to a variety of mediators induced by microorganisms and acting through different pathways, PMN from the blood are attracted to the site of infection where they attempt to destroy the infectious agent by phagocytosis and the release of various lethal mediators. When carefully regulated this response is crucial to the host defense against microorganisms. However, when uncontrolled, PMN activation and infiltration can cause severe tissue damage and lead to complications such as acute respiratory distress syndrome (ARDS) and multiple organ failure. Despite its clinical importance, the regulation of neutrophil migration remains poorly understood. We have observed that E. coli that differ on the basis of expression of a K1 capsule use different mechanisms to escape the host's innate immune response. E. coli that lack a K1 capsule cause a delay in neutrophil recruitment early in infection, allowing these E. coli to divide and overwhelm the host before the neutrophils can get to the site of infection to clear the bacteria. In addition, we show that the LPS receptor, CD14, plays a major role in delaying the recruitment of PMN since deletion of this gene allows early recruitment and enhanced bacterial clearance. This enhanced clearance requires expression of TLR4, since deletion of TLR4 results in early PMN recruitment but no enhanced clearance. In contrast, infection with E. coli expressing a K1 capsule results in early PMN recruitment to the site of infection in the presence or absence of CD14 or TLR4, but early recruitment in this case does not aid in bacterial clearance since the K1 capsule makes these E. coli resistant to phagocytosis. The proposed studies are focused on defining the innate immune mechanisms that prevent or induce early neutrophil recruitment and bacterial clearance in severe infection by defining new pathways and receptors that regulate these critical biological functions. Understanding these molecular events will enable the development of more precise and effective tools for the treatment of sepsis and septic shock. PUBLIC HEALTH RELEVANCE: Sepsis, characterized by a systemic bacterial infection, can lead to life-threatening conditions including multiorgan failure and septic shock. The neutrophil is an important cell that serves as a first line of defense against invading bacteria. This proposal aims to identify the molecules and mechanisms that regulate neutrophil recruitment to the site of infection.

描述（由申请人提供）：败血症，以全身细菌感染和全身炎症反应综合征（SIRS）为特征，可导致危及生命的疾病，包括多器官衰竭和感染性休克。越来越明显的是，有效清除微生物的能力可能是预防败血症和感染性休克引起的发病率和死亡率的最重要因素之一。中性粒细胞（PMN）在这个过程中起着至关重要的作用。为了响应微生物诱导的多种介质并通过不同途径起作用，来自血液的PMN被吸引到感染部位，在那里它们试图通过吞噬和释放各种致命介质来破坏感染原。如果仔细调节，这种反应对宿主防御微生物至关重要。然而，如果不加以控制，PMN的激活和浸润可引起严重的组织损伤，并导致急性呼吸窘迫综合征（ARDS）和多器官衰竭等并发症。尽管其临床重要性，中性粒细胞迁移的调节仍然知之甚少。我们已经观察到，基于K1胶囊表达不同的大肠杆菌使用不同的机制来逃避宿主的先天免疫反应。缺乏K1胶囊的大肠杆菌在感染早期会导致中性粒细胞招募的延迟，使这些大肠杆菌在中性粒细胞到达感染部位清除细菌之前分裂并压倒宿主。此外，我们发现LPS受体CD14在延迟PMN的募集中起主要作用，因为该基因的缺失允许早期募集和增强细菌清除。这种增强的清除需要TLR4的表达，因为TLR4的缺失会导致早期PMN的募集，但不会增强清除。相比之下，无论CD14或TLR4存在与否，表达K1胶囊的大肠杆菌感染都会导致PMN早期募集到感染部位，但在这种情况下，早期募集并不有助于细菌清除，因为K1胶囊使这些大肠杆菌对吞噬具有抗性。拟议的研究重点是通过定义调节这些关键生物学功能的新途径和受体，定义先天免疫机制，以防止或诱导严重感染中的早期中性粒细胞募集和细菌清除。了解这些分子事件将有助于开发更精确和有效的工具来治疗败血症和感染性休克。