Heme-Based Immune Dysregulation in Critical Illness - PROJECT ABSTRACT This NIGMS MIRA will support an Early Stage Investigator and help bridge the widening gap between cutting-edge research and improving patient care in the field of hematology-immunology-infectious diseases, through the investigation of heme dysregulation of the innate and adaptive immune system in patients with sepsis or chronic hemolytic diseases ± red blood cell (RBC) transfusion as a function of circulating heme availability. Sepsis is an invasive infectious disease associated with dysregulated systemic inflammation and more than 4 million deaths worldwide per annum. Specific targeted therapies are lacking. Likewise, in chronic hemolytic diseases such as Sickle Cell Disease (SCD) and Thalassemia, > 50,000 patients have died over the past twenty years. Many patients (~50% in sepsis and >80% in chronic hemolytic diseases) receive a RBC transfusion as supportive therapy or have ongoing ‘low levels’ of intravascular hemolysis. Recent evidence from our laboratory indicate that this hemolysis may further disrupt a patient’s immune system and lead to worse outcomes. This disruption may be causally linked to release of free heme from the underlying hemolysis. We have recently shown that repetitive heme exposure may tolerize the innate and adaptive immune response rendering the host immunosuppressed, which may explain why these patients are at high risk for infection. This proposal will explore a causal relationship in human samples between dysregulated plasma heme metabolism in states of hemolysis (both acute and chronic) and after RBC transfusion that lead to altered host immunity (potentially via TLR4 binding or co-stimulation), further exacerbate inflammation, and worsen outcomes. Program 1 will establish new understandings on relevant heme binding capacity and affinity during critical illness and homeostasis. This overarching goal will define the effects of heme trafficking in plasma from RBC transfusion in sepsis in comparison to chronic hemolytic diseases (hemoglobinopathies) by further refining how binding protein-affinity for heme are affected by conditions of stress (sepsis, transfusion) compared to homeostatic conditions. Second, we hope to further characterize how heme circulates in plasma with differing binding molecules and whether this binding affect direct activation or suppression of canonical innate and adaptive host immunologic pathways (Program 2). Finally, our program will develop new strategies in humans (ex vivo) to scavenge circulating heme or block relevant molecular heme-immune pathways to mitigate negative immune alterations. Collectively, the PI, as an Early-Stage Investigator under this NIGMS MIRA, will close major gaps in knowledge in heme metabolism and its impact on immune activation, providing key insights into acute and chronic effects resulting from exposure to circulating heme in sepsis, SCD, critical illness, or after RBC transfusion. The mechanistic understandings gained from these studies will help develop novel therapeutics to minimize the morbidity and mortality of at-risk patients.
