Role of CD14 and other innate immune receptors in severe sepsis

描述(申请人提供)：败血症，以全身性细菌感染和全身性炎症反应综合征(SIRS)为特征，可导致危及生命的情况，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)在这一过程中起着至关重要的作用。在微生物诱导的多种介质的作用下，血液中的PMN通过不同的途径被吸引到感染部位，在那里它们试图通过吞噬和释放各种致命性介质来破坏感染性介质。如果受到仔细的调控，这种反应对宿主抵御微生物的防御至关重要。然而，如果不加以控制，PMN的激活和渗透可能会导致严重的组织损伤，并导致急性呼吸窘迫综合征(ARDS)和多器官衰竭等并发症。尽管中性粒细胞迁移具有重要的临床意义，但对其调控仍知之甚少。我们观察到，在K1囊膜表达基础上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，我们还发现，内毒素受体CD14在延缓PMN的募集中发挥了重要作用，因为该基因的缺失可以使PMN早日募集并增强细菌的清除。这种增强的清除需要TLR4的表达，因为TLR4的缺失会导致PMN早期招募，但不会增强清除。相反，感染表达K1胶囊的大肠杆菌会导致PMN在CD14或TLR4存在或不存在的情况下早期重新聚集到感染部位，但这种情况下的早期重新聚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产生抵抗。建议的研究集中在通过定义调节这些关键生物学功能的新的途径和受体来确定在严重感染中防止或诱导早期中性粒细胞募集和细菌清除的先天免疫机制。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。 公共卫生相关性：以全身性细菌感染为特征的败血症可导致包括多器官衰竭和感染性休克在内的危及生命的情况。中性粒细胞是一种重要的细胞，是抵御入侵细菌的第一道防线。这项建议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.