Role of CD14 and other innate immune receptors in severe sepsis

描述（由申请方提供）：脓毒症的特征为全身细菌感染和全身炎症反应综合征（SIRS），可导致危及生命的疾病，包括多器官衰竭和脓毒性休克。越来越明显的是，有效清除微生物的能力可能是预防脓毒症和脓毒性休克所致发病率和死亡率的最重要因素之一。中性粒细胞（PMN）在这一过程中发挥着重要作用。响应于由微生物诱导并通过不同途径起作用的各种介质，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作用和释放各种致死介质来破坏感染因子。当仔细调节时，这种反应对于宿主防御微生物至关重要。然而，当不受控制时，PMN的激活和浸润可引起严重的组织损伤并导致并发症，如急性呼吸窘迫综合征（ARDS）和多器官衰竭。尽管其临床意义，中性粒细胞迁移的调节仍然知之甚少。我们观察到E.大肠杆菌的K1荚膜表达不同，使用不同的机制来逃避宿主的先天免疫反应。E.缺乏K1荚膜的大肠杆菌在感染早期导致中性粒细胞募集延迟，使得这些大肠杆菌。在中性粒细胞到达感染部位清除细菌之前，大肠杆菌分裂并压倒宿主。此外，我们发现，LPS受体，CD14，起着重要作用，在延迟招聘的中性粒细胞，因为删除该基因允许早期招聘和增强细菌清除。这种增强的清除需要TLR4的表达，因为TLR4的缺失导致早期PMN募集，但没有增强的清除。相比之下，感染E.表达K1荚膜的大肠杆菌在存在或不存在CD14或TLR4的情况下导致早期PMN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荚膜使这些大肠杆菌在感染部位的细胞增殖。对吞噬作用有抵抗力的大肠杆菌。拟议的研究重点是定义先天免疫机制，通过定义调节这些关键生物学功能的新途径和受体，预防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脓毒症和脓毒性休克。 公共卫生相关性：脓毒症的特征是全身性细菌感染，可导致危及生命的疾病，包括多器官衰竭和脓毒性休克。中性粒细胞是一种重要的细胞，作为抵御入侵细菌的第一道防线。该提案旨在确定调节中性粒细胞募集到感染部位的分子和机制。

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.