Sepsis is a leading cause of death that kills more than 5 million people annually word-wide. Sepsis involves immune dysfunction that is characterized by excessive inflammation that causes multiple organ dysfunction syndrome (MODS). At the same time, immunosuppression and T cell dysfunction impair host immune defenses, resulting in the unimpeded spread of bacterial infections. Despite intense research efforts in the field, all previous attempts to improve outcome in sepsis have failed and no effective treatments are available. These disappointing results clearly demonstrate the need for a better understanding of the underlying mechanisms that cause immune dysfunction in sepsis. The focus of this laboratory has been to determine the molecular and cellular mechanisms that cause immune dysfunction in trauma, critical care, and sepsis patients. Our long-term goal is to identify novel pharmacological strategies that can prevent excessive inflammation and the immunosuppression responsible for morbidity and mortality in sepsis. We discovered novel signaling mechanisms that regulate neutrophils and T cells and that represent promising therapeutic targets to restore immune homeostasis in sepsis patients. These novel signaling mechanisms regulate cell functions by cellular ATP release and by autocrine feedback through excitatory and inhibitory purinergic receptors that act in synergy with Ca2+ signaling and mitochondrial metabolism to fine-tune the immune cell responses needed for host defense. We found that the subcellular localization and differential activation of mitochondria and purinergic receptors are essential for proper neutrophil and T cell functions. Interfering with these signaling processes impairs the ability of these cells to detect and eliminate invading pathogens. We found that these novel cell signaling pathways are impaired in sepsis patients because excessive systemic ATP that accumulates in the circulation of these patients interferes with the autocrine purinergic signaling mechanisms that regulate immune cell functions. In addition, we found that sepsis impairs the mitochondria that provide the ATP for these purinergic signaling mechanisms. In the proposed MIRA project, we plan to continue our studies in order to define the molecular and cellular mechanisms that lead to immune dysfunction in sepsis. NAD is a nucleotide that functions as a coenzyme for many metabolic processes. We will examine whether and how declining NAD levels in sepsis contribute to mitochondrial dysfunction, immune defects, and poor outcome in sepsis. We will study whether increased expression of CD38 in sepsis is responsible for increased NAD consumption and whether NAD consumption deprives sirtuins of the coenzyme they need to prevent mitochondrial damage and prevent immune cell dysfunction. In addition, we will study how purinergic signaling contributes to the activation and trafficking of mitochondria within T cells and neutrophils and how these regulatory mechanisms are impaired in sepsis. Finally, we will explore how CD38, NAD, and sirtuins can be targeted with pharmacological interventions in order to restore mitochondrial function, purinergic signaling, and immune homeostasis in sepsis patients. The proposed work is innovative and possibly paradigm shifting because it focuses on the novel concept that mitochondria are central regulators of immune cells and that mitochondrial dysfunction is the underlying problem that impairs immune function in sepsis. We propose to exploit this knowledge with innovative treatments that replenish mitochondrial health and purinergic signaling and thereby restore immune function from within the cell. This approach is superior to previous strategies aimed at intercepting stimulatory immune cell signals that failed because these strategies further disrupted immune homeostasis and the ability of the host to fight infections.
Sepsis is a highly lethal disorder due to uncontrolled infection and multiple organ dysfunction. It is the major cause of death in most intensive care units in the United States. This program seeks to identify novel immune therapies that will reduce the risk of organ failure and improve the ability of patients to respond to and eliminate invading microorganisms.
