DESCRIPTION (provided by applicant): My goals as a physician-scientist are to perform laboratory research that will advance the field, and improve the care of my patients. The combination of my background in Infectious Disease and Critical Care medicine gives me unique perspective from which to study the clinical problem of sepsis. I will spend approximately 75% of my time pursuing scientific research, and the remainder as a critical care attending in the intensive care units which will reinforce my focus on studies of sepsis. The K08 award will enable me to expand my studies of regulation of the immune response by costimulatory receptors during sepsis and investigate the modulation of costimulatory molecule expression as a potential form of tailored immunotherapy for septic patients. During this time I will further develop my research career though: 1) participation in weekly immunology seminars and formal coursework; 2) augmentation of my technical skills by attending advanced training courses in flow cytometry; and 3) attendance and presentation of my work at IDSA, SCCM and Shock Society conferences. My long term objective is to obtain RO1 level funding and transition from a mentored research environment to independent investigator. The proposed project will investigate the mechanistic role of costimulatory molecules (CSM) in the immune response during sepsis, and the ability of Toll-like (TLR) and adenosine receptor mediated activity to regulate expression of these molecules. The role of CSM to determine the dynamics of the immune response and survival of the septic host has not been defined. TLRs function as early detectors of infection through recognition of microbial products and help initiate an immune response through stimulating the release of inflammatory cytokines and upregulation CSM on antigen presenting cells (APCs). Recent work has shown that adenosine receptors have the capacity to modulate CSM expression on APCs and lymphocytes. Our group has found that septic mice lacking the adenosine 2A or 2B receptor or who receive pharmacologic blockade of A2BR have improved clearance of infection and survival. Using a well characterized mouse model of sepsis of cecal ligation and puncture (CLP) we will 1) Study the expression of different CSM longitudinally in septic mice and determine their association with pro and anti-inflammatory cytokine levels in plasma, ability to clear infection, and T cell proliferation and effector function, 2) Determine if activating or blocking specific TLRs and adenosine receptors singly, or in combination alters CSM expression and improves clearance of infection and survival in a CLP model of sepsis, and 3) Determine if direct manipulation of CSM expression improves immune function during sepsis to decrease bacterial load and increase survival. Together these experiments will characterize the role of CSM in the immune response to sepsis, and determine if pharmacologic modulation of CSM expression is a potential therapeutic intervention.

There are increasing numbers of patients admitted to the hospital with sepsis and the mortality still remains extremely high at 30-50%. In addition more people are undergoing medical treatment resulting in suppression of the immune defenses, thus making them more vulnerable to infections which will likely further increase the incidence of sepsis. We still do not have a complete understanding of the many complex interactions involved in the immune response which limits our ability to treat these patients therefore it is vital that further work be done in order to develop new treatments for sepsis.