Immune Function in Sepsis: Role of Sirtuin

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Decades long effort to translate pre-clinical research into treatments have failed; there are no effective molecular-targeted therapies to treat sepsis. Substantial progress in supportive treatments with fluid resuscitation, timely antibiotics have decreased acute-phase mortality but now a significant proportion of sepsis and septic shock victims develop, chronic critical illness (CCI). During CCI, the long term mortality increases from secondary infections and cardiovascular causes. Predicting ultimate fate of sepsis patients, survival versus death or CCI and ability to respond to secondary infections is difficult. Immune response in sepsis undergoes a dynamic reprogramming from hyper-inflammation with immune resistance of pathogen that gives way to a hypo-inflammatory response with immune tolerance, within hours/days. Leukocyte adhesion, earliest in vivo inflammatory response, is instrumental to the “resistance” vs. “tolerance” and serves as a “window” to the host immune response. Sirtuins (SIRTs), a highly conserved family or proteins regulate the shift from hyper- to hypo- inflammation, including leukocyte adhesion in rodent sepsis. This project will focus on two basic strategies in to identify the hyper- vs. hypo-inflammatory phase and treat in a phase-specific manner. Project 1: Establish temporal based physiological marker and biomarkers to distinguish sepsis phases (GAP 1): Under this aim, we will establish: 1) A rapid in vitro assay of leukocyte (peripheral blood mononuclear cells: PBMC) adhesion response to secondary stimuli and 2) SIRT1 and SIRT2 as biomarkers, to identify hypo-inflammatory phase of sepsis. We will study adhesion response and SIRT biomarker profile during sepsis/septic shock progression in each patients at least at three different time points and correlate the profile changes with clinical outcomes. Project 2: Determine the effect of temporal based phase-specific modulations of SIRT1 and 2 on response to secondary stimuli (Gap 2): Using patient PBMCs (monocytes) at different time points during sepsis/septic shock progression and treating with SIRT1 and SIRT 2 activation/inhibition with genetic and pharmacological approaches, I will study the effect of SIRT modulation on: 1) Monocyte-endothelial cell adhesion response to secondary stimuli, 2) Immune response and 3) Bioenergy and metabolic responses during sepsis progression. Impact: The completion of these studies will 1) Identify markers/biomarkers to identify sepsis phases, 2) Correlate the immuno-metabolic response profile of PBMCs during sepsis progression and patient outcomes, 3) Identify SIRTs 1 and 2 (and potentially other metabolic/inflammatory molecules) as phase-specific therapeutic agents.