Nosocomial infections (NI) during hospitalization in the intensive care unit (ICU) are a significant proportion of health-related cost, morbidity, and mortality in critically injured adults and children. Studies have shown that critical illness can induce a clinically significant form of innate immune suppression that increases susceptibility to NI. Innate immune cell responses to pathogen invasion are the first line of defense against NI. Currently, defects in innate immune function in patients cannot be determined using standard laboratory tests. Additionally, there are no approved therapies targeted to enhance innate immune function and reduce susceptibility to NI. Early experimental evidence indicates there is a reduced ability leukocytes from whole blood, when stimulated by LPS ex vivo, to produce the pro-inflammatory cytokine tumor necrosis factor alpha (TNF?) in critically injured children who develop NI. There is also preliminary evidence that the immunostimulating agent granulocyte-macrophage colony stimulating factor (GM-CSF) can improve TNF? production capacity in leukocytes from whole blood of the critically ill. In addition to cytokine production, phagocyte function is also vitally important in clearance of infection and has not been explored in the context of traumatic injury. To evaluate phagocyte function we plan to measure the ability of leukocytes in whole blood to perform the critical antimicrobial functions of phagocytosis and killing in a mouse model of injury-induced immune suppression (partial hepatectomy), and hypothesize that phagocyte function is also suppressed following injury. We then plan to determine whether immunostimulation with GM-CSF will improve phagocyte function in this model. Moreover, we will evaluate the ability of GM-CSF to reduce the severity of experimentally induced nosocomial infection (urinary tract infection) following surgical injury. Therefore, the objectives of the research training proposal are: 1) to characterize innate immune functions of phagocytes against known nosocomial pathogens;2) to evaluate the effects of GM-CSF on the antimicrobial functions of phagocytes and;3) determine ability the of GM-CSF to reduce the severity of NI in our animal model of injury- induced immune suppression. The findings will inform subsequent studies focused on detecting and reducing risk for NI in critically ill children. The applicant's career goal is to conduct interdisciplinary translational research ina pediatric intensive care setting of a major academic medical center. The training plan and interdisciplinary mentorship team have been carefully crafted to ensure completion of the study aims, and to provide comprehensive training in laboratory measures of innate immune cell function. This training will provide the tools to launch a successful career as a nurse-scientist focused on improving nursing care outcomes for critically ill children at high risk for developing NI.
Knowledge gained from this proposal could impact the health of the public and reduce health care costs by providing new methods for monitoring of innate immune function to identify intensive care unit patients at highest risk for contracting a nosocomial infection. In addition, public health could be affected through the investigation of an immune modulating agent for the purposes of improving immune function to decrease nosocomial infection risk.
