Training Innate Immunity: A new approach to the treatment of Sepsis

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This revised competitive renewal application is submitted under the NIH multiple PI initiative (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html). Drs. Ed Sherwood and David Williams will serve as the PIs. The multiple PI strategy is advantageous because it enables a “team science” approach that will draw equally on the expertise and experience of both of the PIs, their research groups and their respective institutions. The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome, septic shock and/or multiple organ dysfunction syndrome. In the United States ~951,000 patients/year develop sepsis with approximately half of these patients in the ICU and an overall mortality rate is 28.6%. Those patients that survive the initial septic event may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due to immune dysfunction. It is well accepted that sepsis causes suppression of the immune system and that sepsis-induced immunoparalysis predisposes the critically ill patient to secondary infections. Attempts at developing effective therapies to prevent or treat sepsis and its associated immunosuppression have proven to be exceedingly difficult. In fact, no drugs are currently approved by the FDA for the management of sepsis. Recent data have provided compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to pathogens. In this revised application, we propose the novel concept that it may be possible to “train” the compromised immune system, such that an effective response can be mounted to existing and/or subsequent infections. We hypothesize that “innate immune training will reprogram the metabolic, transcriptomic, epigenomic and functional phenotype of monocytes and macrophages from patients with sepsis and confer augmented resistance to infection”. To critically evaluate this hypothesis, we propose the following specific aims. Aim 1. Define the functional role of β-glucan-induced metabolic reprogramming for inducing and sustaining trained immunity in human monocytes and macrophages. In this aim, we will explore the cellular and molecular mechanisms that are essential for induction of the trained phenotype. Specifically, we will investigate the metabolic phenotype of trained human monocyte/macrophages and determine the functional importance of metabolic reprogramming for inducing and sustaining the trained phenotype in leukocytes. Aim 2. Elucidate the mechanisms of innate immune training in human adults as a function of age. In this aim, we will examine the impact of immune training on leukocytes from aging humans. In ex vivo experiments, we will examine cytokine secretion, metabolic reprogramming, gene expression, the epigenome, mitochondrial function and the anti-microbial functions of human monocytes and macrophages in response to immune training. Aim 3. Examine the effect of immune training in leukocytes isolated from sepsis patients. In this aim, we will employ monocytes or monocyte derived macrophages from sepsis patients. We will examine the effect of immune training on metabolic reprogramming, gene expression, the epigenome, mitochondrial activity and functionality of human monocytes and macrophages from septic patients. Successful completion of this research will provide a wealth of new and novel information on the mechanisms driving trained immunity in the presence and absence of sepsis. Of greater significance, this research will investigate innate immune training as a strategy for preventing and/or ameliorating sepsis and septic sequelae in the critically ill patient.