This is an application for a K08 Career Development Award for Philip A. Verhoef, MD, PhD. Dr. Verhoef is an immunologist and an ICU physician in the adult and pediatric critical care units at the University of Chicago. He is building a career a a translational immunologist-intensivist, capable of bringing cutting edge immunology from the bench to the ICU bedside in order to understand the devastating disease of sepsis. This K08 award will provide Dr. Verhoef with the support necessary to achieve the following goals: 1) extend his experience in innate murine immunology to the use of mouse models of sepsis for understanding immunologic dysregulation underlying sepsis mortality; 2) develop expertise in the collection and immunologic analysis of samples from critically ill patients, and 3) utilize lare datasets to explore biologically relevant associations between complex diseases. To achieve these goals, Dr. Verhoef has assembled a mentoring team led by primary mentor, Dr. Anne Sperling, who is a pulmonary immunologist with experience in both mouse and human cellular immunology with, co-mentor Dr. Juliane Bubeck Wardenburg, who is an immunology-trained microbiologist and Section Chief of Pediatric Critical Care with expertise in host-pathogen interactions, and three advisors: Dr. Gokhan Mutlu, who is the Section Chief of Pulmonary/Critical Care and an expert in lung injury; Dr. Julian Solway, who is a pulmonologist and Dean of Translational Medicine with skills at assessing large datasets for identification of disease phenotypes; and Dr. Andrey Rzhetsky, a theoretical biologist and a leading expert in the development of novel bioinformatics approaches to complex biology and disease. The proposed research in this application will be conducted at the University of Chicago, one of the nation's leading private universities and home to renowned divisions of immunology, pulmonary medicine, bioinformatics, and microbiology, with state-of-the-art facilities to enable cutting-edge research. Sepsis remains an important cause of morbidity and mortality, accounting for more than 10% of all ICU admissions in the USA. One theory of sepsis pathophysiology describes the host's immune response as a balance between pro- and anti-inflammatory signals that simultaneously serve to eliminate the pathogen and resolve tissue destruction caused by both the pathogen and the host's response. While the pro-inflammatory signals typically include type 1 or type 17 responses, the anti-inflammatory signal mediators remain less well understood. Recent evidence suggests that type 2 cytokines, classically associated with Th2 allergic responses, play a role. Dr. Verhoef's central hypothesis is that these type 2 immune responses counter type 17 immune responses during infection, acting to both prevent the development of sepsis and protect against sepsis-associated mortality. Dr. Verhoef's preliminary data indicates that mice with active type 2 inflammation are completely protected from lethal Staphylococcus aureus sepsis. Thus, in Aim 1, he will systematically examine the mechanisms of this novel type 2 immune response protection during sepsis, using murine immunology techniques. In addition, Dr. Verhoef has found that among patients with S. aureus bacteremia, those alive at 90 days had higher numbers of circulating Th2 cells early in their immune response compared with non-survivors, suggesting a protective role for type 2 immune responses. In Aim 2, Dr. Verhoef will use samples from these patients to explore the cellular mechanisms of protective type 2 and S. aureus- specific immune activation, and prospectively validate this approach in newly septic ICU patients. Finally, using large dataset analysis, Dr. Verhoef has found that patients with sepsis are less likely to have comorbid type 2- mediated immune diseases like asthma and allergy, suggesting that these immune responses protect against the development of sepsis. In Aim 3, he will extend these analyses by looking at outcomes from sepsis in hospitalized patients, as a function of either type 2 immune response biasing or cause of infection. Thus, Dr. Verhoef is addressing the pathophysiology of sepsis using 3 divergent and complementary methods which capitalize on his training as a clinician and an immunologist, in the environment of a cutting-edge university. This research will form the basis for an R01 grant application focused on integrating epidemiologic predictors of disease and individual cellular immune phenotypes to create a unique, patient-specific immune fingerprint that can be used to develop a precision-medicine approach to diagnosis and treatment of sepsis in the ICU.