Role of CD14 and other innate immune receptors in severe sepsis

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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.