Project Summary/Abstract Sepsis is defined as a dysregulated host inflammatory response that occurs due to life-threatening infection with the presence of organ dysfunction. Sepsis is the most frequent cause of mortality in most intensive care units and is responsible for over a quarter million deaths in the United States annually. The incidence of sepsis is increasing because of the aging population and the associated weakening of the immune system that occurs in the aged. Until recently, most research on sepsis was focused on blocking the initial hyper-inflammatory cytokine-mediated phase of the disorder. Improved treatment protocols have resulted in most patients surviving this initial hyper-inflammatory phase of sepsis and entering a protracted immunosuppressive phase. The majority of deaths in sepsis occur during this immunosuppressive phase of the disorder. Deaths in this immunosuppressive phase of sepsis are typically due to failure to control the primary infection or a result of acquisition of secondary hospital-acquired infections, often with opportunistic pathogens thereby underscoring the host’s impaired immunity. The reactivation of multiple latent viruses including cytomegalovirus and herpes simplex virus that occurs in patients with protracted sepsis further attests to the profound degree of immunosuppression in these patients. There is a growing body of evidence in animal studies as well as data from small phase II clinical trials indicating that therapies which boost the host immune system can improve morbidity and mortality in sepsis. This immuno-therapeutic based approach to sepsis has been the focus of the principal investigator for the last decade. The current proposal is an extension of these investigations. The overarching goal of this proposal is to identify new immuno-adjuvant therapies that restore host immunity, decrease pathogen burden, ameliorate organ injury, and improve survival in sepsis. We are focusing on testing immune modulatory agents that have an excellent safety profile and are in current clinical trials. Just like a finely-tuned orchestra, the immune system functions most effectively when all its various components are working harmoniously. Sepsis induces multiple defects in host immunity and it is likely that combination immunotherapy may offer the best protection in sepsis. Thus, a second major goal of this study is to test combination immunotherapy targeted against specific sepsis-induced defects in innate and adaptive immunity which are believed to play a critical role in compromising host immunity. Successful completion of this study would enable rapid translation of newly identified drugs into clinical trials in sepsis and offer a new way forward against this heretofore intractable disease.