Deciphering how anesthetics increase host susceptibility to microbial infection

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Anesthetic administration is associated with a significantly increased risk of infection in hospital patients undergoing surgery. While several studies have reported linkages between commonly used anesthetics and decreased immune cell function, little is currently known regarding the molecular mechanisms by which drugs that target the nervous system influence host immune responses. An improved understanding of pathways of communication between the nervous and immune systems would clarify how specific anesthetics place individuals at greater risk for microbial infection. The facultative intracellular bacterial pathogen Listeria monocytogenes (Lm) has served for decades as a powerful model system for deciphering host responses to microbial infection, and the organism continues to serve as tool for elucidating new paradigms of innate and adaptive immunity. Based on the well-established mouse model of Lm infection, experiments outlined within this proposal will use Lm to elucidate the mechanisms by which commonly used surgical anesthetics, such as propofol, dramatically increase host susceptibility to microbial infection. Preliminary data indicates that intravenous administration of anesthetics to mice prior to Lm infection increased bacterial burdens in target organs by more than 10,000-fold in comparison to none drug-treated animals. Propofol, the most commonly used anesthetic in human surgeries, was found to reduce the clearance of bacteria from mouse target organs and to alter host innate immune signaling. The working hypothesis of this proposal is that propofol and possibly other anesthetic agents increase host susceptibility to microbial infection by enhancing bacterial translocation across host barriers while also impeding the recruitment of innate immune effector cells to sites of bacterial infection. Experiments in Aim 1 will examine the impact of anesthetic exposure on multiple facets of host immunity to Lm infection, including cytokine and chemokine signaling and monocyte recruitment to sites of bacterial infection. Aim 2 experiments will determine if propofol exposure has broad effects towards increasing host susceptibility to other microbial pathogens, specifically bacteria that occupy different intracellular and extracellular replication niches within the host. The outcome of these pilot studies will be a deeper understanding of how anesthetic agents suppress host immunity, and the data generated will form the basis for future collaborative projects designed to decipher the pathways that link the central nervous system with host immune function. This novel area of research has the potential to ultimately reduce the frequency and severity of post-surgical infections via the recognition of host immune responses negatively impacted by anesthetic exposure and by recognition of the types of infections for which anesthesia increases host susceptibility. PUBLIC HEALTH RELEVANCE: Anesthetic administration is associated with significantly increased rates of infection in hospital patients undergoing surgery. Experiments described within this application will use the model bacterial pathogen Listeria monocytogenes as a well characterized infectious model to decipher the functional links between anesthetic exposure and increased host susceptibility to microbial infection. This information will prove useful for the development of improved strategies to reduce post-surgical infections and improve patient outcomes.