Neutrophils (PMN) play a critical role in the host response to bacterial infection, in part because of their ability to regulate inflammation through cell-cell communication. Microvesicles (MVs) released by activated PMN have emerged as a mediator of immune regulatory signals to other phagocytes such as macrophages (M?). Key knowledge gaps exist in understanding the diversity of PMN MVs released in response to different agonists, the impact of PMN-to-PMN signaling by means of MVs, and the ability of PMN MVs to modulate the inflammatory response, especially in the setting of microbial challenge. The candidate's objective is to assess the impact on phagocyte function of two PMN MV populations ? MVs from PMN stimulated with N-formylmethionyl-leucyl-phenylalamine, and from PMN stimulated with S aureus. The hypothesis is that PMN MVs modulate phagocyte inflammatory tone and response to bacterial pathogens. The rationale is to understand a tool used by PMN to influence the innate immune system during infection. In order to test the hypothesis, the candidate will pursue two specific aims:
Aim 1 : To define the nave PMN response after exposure to PMN MVs Aim 2: To determine how PMN MVs modulate M? inflammatory signaling This proposal is innovative because it investigates novel roles for PMN MVs in modifying phagocytic function in nave PMN, priming the PMN NADPH oxidase, and upregulating phagocyte antimicrobial function. The contribution of this proposal is significant because determining the mechanisms of an integral component of immune function in the setting of infection will guide potential therapeutic interventions. Deficiencies in the ability of the human immune system to clear bacterial infection and terminate the inflammatory response are likely factors in the high morbidity and mortality of sepsis. The career goal of the candidate is to be a physician-scientist whose work at the bench will inform clinical practice. The current K08 application describes a research project that will enable the candidate to develop the intellectual, professional and technical skills to navigate this critical period of transition towards becoming an independent investigator. The candidate's mentor is an expert in the field of neutrophil biology with experience in training junior physician-scientists. As a member of the Iowa Inflammation Program, the candidate will have access to its skilled investigators, resources, and culture of collaboration. This K award will therefore be a defining step in the career path of the candidate.
Activated neutrophils release microvesicles, and our preliminary data demonstrate an effect of these microvesicles on neutrophil phagocytic ability and NADPH oxidase priming as well as on macrophage cytokine release and bacterial killing. We propose studies to determine how neutrophils employ microvesicles to mediate the functions of nave neutrophils and macrophages, emphasizing the phagocyte inflammatory response and the phagocyte response to bacteria, using S aureus as a model pathogen. Completion of this project will yield insights into how neutrophils control infection and regulate the process of inflammation.
