This 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 with 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 as well as 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. The 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 following treatment with Dectin-1 agonists. We have successfully synthesized Dectin-1 ligands that increase resistance to sepsis. In this application, we propose the novel concept that it may be possible to train the compromised immune system with synthetic Dectin-1 ligands, such that an effective response can be mounted to existing and/or subsequent infections. We hypothesize that immunologic training and metabolic reprogramming will decrease septic morbidity and mortality in clinically relevant models of sepsis and augment host immunity in vulnerable populations. To critically evaluate this hypothesis, we propose the following specific aims.
Aim 1. Determine the effects of immune training on sequelae and outcomes in CLP-induced polymicrobial sepsis.
This aim will define the efficacy of immune training in murine model of polymicrobial sepsis. Specifically, this aim wil determine if synthetic Dectin-1 agonists can train the immune system to prevent and/or treat polymicrobial sepsis.
Aim 2. Determine the effect of immune training on sequelae and outcomes in a clinically relevant model of post-burn immunosuppression.
This aim will establish whether training will improve survival in clinically relevant model of post-burn immunosuppression.
Aim 3. Establish the impact of training on innate immune parameters in sepsis.
This aim will define the alterations in innate immune function by which training augments the host response to infection.
Aim 4. Define the mechanisms by which synthetic Dectin-1 ligands induce trained immunity.
This aim will define the specific signaling alterations by which immune training enhances antimicrobial responses in populations that are at high risk of developing infections.
The critically ill patient frequently develops a complex disease spectrum that may include respiratory distress, systemic inflammation, infection, shock and failure of major organs. In the United States ~951,000 patients develop this disease every year. Approximately 28.6% of these patients die. Those patients that survive may die due to widespread organ failure or due to prolonged immune suppression that can lead to opportunistic infection. In addition, patients that survive sepsis frequently have long term physical and neurological disabilities. The estimated cost of this disease is approximately $20 billion/year. At present, there are no drugs approved for the treatment or management of this disease. It is clear that new and novel approaches to the treatment of sepsis are needed. To address this pressing problem, we propose the novel concept that it may be possible to 'train' the compromised immune system, such that it can prevent or significantly reduce this deadly and costly disease. Specifically, we propose to develop new and novel drug candidates that can effectively 'train' the immune system so that the critically ill patient has increased resistance t this disease.
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