Comparison of the Dysregulated and Regulated Host Responses to Infection

Project Summary/Abstract: Comparison of the regulated and dysregulated host response to infection Brief Background: Sepsis is life-threatening organ dysfunction caused by an extensively studied but poorly understood dysregulated host response to infection. Specific therapy has focused on modifying the sepsis- associated immune response; the failures of these interventions despite promising early data has been confounding and disheartening. One possible solution lies in the definition itself. The existence of a dysregulated host response implies that there is a regulated host response. Thus, control data for sepsis studies should come from cohorts of animals or patients who are infected but never develop the life- threatening organ dysfunction that defines sepsis and therefore have a regulated host response. This regulated immune response to uncomplicated infection, once a major focus of investigation, has not been closely examined in the context of our enhanced understanding of immunology or with application of newly available advanced molecular techniques. Here, we propose a new lens for sepsis studies by using the regulated host response as the comparison group for sepsis in mice and human studies. Our preliminary data suggests that there is impaired IL-10 production by T cells in our mouse model of sepsis and in patients with sepsis. Thus, we hypothesize that one difference between the regulated immune response to infection and the dysregulated response of sepsis is insufficient IL-10-mediated signaling by CD4 T cells. To initiate our investigations, we propose these Specific Aims: 1. To compare the effects of uncomplicated infection and sepsis on factors effecting transcriptional families associated with IL-10 transcription in CD4 T cells and regulatory T cells. 2. To analyze the effects of IL-10 modulation on lung, heart, liver, and kidney function in mice with either uncomplicated infection or sepsis. These aims will provide insight into the immunological differences between a regulated and dysregulated host response to infection. In recent years, identification of subphenotypes within a heterogenous disorder has profoundly altered our understanding of disease. This proposal is significant because the use of a refined control group may allow us to distinguish between which prior observations in sepsis represent maladaptive versus adaptive behavior. Interventions alter either process may have long-term effects on immune function and could be manipulated to treat inflammatory illnesses. This proposal will allow Dr. Fisler, a clinical pediatric intensivist, to develop a unique skill set that will enable her to effectively research sepsis immunology. Completing these experiments at the Feinstein Institutes for Medical Research with the support of a dedicated mentorship team and access to a strong didactic education will be crucial in Dr. Fisler’s career development and is a critical step towards becoming an independent researcher in sepsis and organ dysfunction.