While through efforts like the Surviving Sepsis Campaign and others, supportive therapies have improved survival of the critically ill septic patient, nonetheless, a substantial number still develop this morbid syndrome and die. Unfortunately, there presently exists no true medicinal/ molecular therapeutic agent that can be applied to treat sepsis or diagnosis/ prognosis (beyond Pro-calcitonin) the trajectory of the critically ill patient. Thus, the need remains to further clarify the complex pathobiology of the septic process. In this respect, our laboratory has had sustained interest in understanding how sepsis, as produced by cecal ligation and puncture (CLP), differentially effects the immune response observed in divergent tissue sites. Importantly, we have observed that CLP induces marked changes in the functional responsiveness of monocyte/ macrophages, as well as in key regulatory T-cell populations, i.e., invariant natural killer T (iNKT)-cells and CD4+CD25+ native T- regulatory (T-reg)-cells (within the spleen, liver and intestine), which we have found to either have the ability to induce marked immune suppression or have an effect on the animal's capacity to ward off septic morbidity/ mortality. Most significantly, we have recently shown that a novel family of co-inhibitory molecules/ receptors as well as their cell-associated ligands, belonging to the Programmed Cell Death Receptor family, appear to be playing a unique and very proximal role in both immune cell/ organ morbidity and mortality seen not only in experimental septic mice, but their increased expression is associated with poor outcome in critically ill patients. With this in mind, we propose the following hypothesis that classic adaptive/ lymphoid co- inhibitory receptors, such as programmed cell death receptor (PD)-1 and B &T lymphocyte attenuator (BTLA) and/or their ligands (PD-L1 or PD-L2 for PD-1 &HVEM for BTLA), contribute to the development of septic morbidity via their novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune/ non-immune (endothelial and/or epithelial) cells present in a given tissue.
In AIM 1 : We will establish the extent to, which macrophages, neutrophils and regulatory lymphoid cell's expression of PD-1 and/or BTLA contributes to the development of immune cell dysfunction in sepsis.
AIM 2 : We will determine how and what non-immune cells express the ligands for PD-1 or BTLA, i.e., PD-L1, PD-L2 and/or HVEM, respectively, following the onset of sepsis;how this contributes to the development of organ dysfunction and/or subsequent survival of sepsis;and what the significance of this expression is to liver or intestinal endothelial and/or epithelial cell dysfunction seen in sepsis. We firmly believe the results of these studies will provide information that not only allows us to better understand the pathobiology of sepsis both experimentally in mice and critically ill patients, but also point to agents that can be used to possibly diagnose, prognosticate and/or therapeutically inhibit the progression of sepsis.

Public Health Relevance

Despite the use of specific antibiotics, aggressive operative intervention, nutritional support and recently, antibodies against endotoxin, activated protein C and anti-cytokine therapies in septic patients, multiple organ failure continues to be a major cause of morbidity/ mortality in the surgical intensive care unit. Thus, it is essential to determie in depth the mechanism(s) underlying the patho-physiology of sepsis so that more appropriate therapeutic interventions can be designed. We propose to determine the impact of a novel family of cell-associated co-inhibitor molecules/ ligands, on the development of immune/ organ dysfunction/injury and death resulting from sepsis. The contribution of these molecules to the development of both septic morbidity and mortality will be examined in the setting of experimental sepsis using genetically altered mice as well as drug interventions directed at genes or mediators thought to be involved in the regulation of these cells. We believe that these studies will provide new and useful mechanistic information concerning the patho-biology of sepsis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Dunsmore, Sarah
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Rhode Island Hospital
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Biron, Bethany M; Chung, Chun-Shiang; Chen, Yaping et al. (2018) PAD4 Deficiency Leads to Decreased Organ Dysfunction and Improved Survival in a Dual Insult Model of Hemorrhagic Shock and Sepsis. J Immunol 200:1817-1828
Chun, Tristen T; Chung, Chun-Shiang; Fallon, Eleanor A et al. (2018) Group 2 Innate Lymphoid Cells (ILC2s) Are Key Mediators of the Inflammatory Response in Polymicrobial Sepsis. Am J Pathol 188:2097-2108
Fallon, Eleanor A; Biron-Girard, Bethany M; Chung, Chun-Shiang et al. (2018) A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis. J Leukoc Biol :
Cheng, Tingting; Bai, Jianwen; Chung, Chun-Shiang et al. (2018) Herpes Virus Entry Mediator (HVEM) Expression Promotes Inflammation/ Organ Injury in Response to Experimental Indirect-Acute Lung Injury. Shock :
Biron, Bethany M; Chung, Chun-Shiang; O'Brien, Xian M et al. (2017) Cl-Amidine Prevents Histone 3 Citrullination and Neutrophil Extracellular Trap Formation, and Improves Survival in a Murine Sepsis Model. J Innate Immun 9:22-32
Wang, Fei; Huang, Xin; Chung, Chun-Shiang et al. (2016) Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis. Am J Physiol Gastrointest Liver Physiol 311:G237-45
Cheng, Tingting; Bai, Jianwen; Chung, Chun-Shiang et al. (2016) Enhanced Innate Inflammation Induced by Anti-BTLA Antibody in Dual Insult Model of Hemorrhagic Shock/Sepsis. Shock 45:40-9
Young, John S; Heffernan, Daithi S; Chung, Chun-Shiang et al. (2016) Effect of PD-1: PD-L1 in Invariant Natural Killer T-Cell Emigration and Chemotaxis Following Sepsis. Shock 45:534-9
Biron, Bethany M; Ayala, Alfred; Lomas-Neira, Joanne L (2015) Biomarkers for Sepsis: What Is and What Might Be? Biomark Insights 10:7-17
Hutchins, Noelle A; Unsinger, Jacqueline; Hotchkiss, Richard S et al. (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224-33

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