Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis Pathobiology

ABSTRACT Earlier recognition of sepsis and improved implementation of best practices have significantly reduced in-hospital mortality over the past decade. As in-hospital survival has improved, the number of patients who do not fully recover has dramatically increased; nearly 50% of surgical sepsis patients will never fully recover and nearly one-third of these patients will die within 6 months. Currently, one important critical question that vexes medical practitioners is: why do some surgical sepsis patients rapidly recover while others have poor long-term outcomes despite our best supportive efforts? Why are some of our comorbid (i.e. cancer, end-stage renal disease, etc.) populations at increased risk of nonrecovery? Our overarching hypothesis is that the consequences of surgical sepsis (death and poor quality of life) are the result of an unresolving host leukocyte dyscrasia, similar to other chronic conditions such as cancer and autoimmune disease. Specifically, the preferential expansion and self-perpetuation of myeloid-derived suppressor cells (MDSCs), propagated in part through epigenetic changes in both bone marrow (BM) progenitors and MDSCs, drives non-acute infectious and noninfectious complications after sepsis. This Program will investigate in human surgical sepsis the underlying mechanisms that drive ‘dysfunctional myelopoiesis’, expansion of MDSC populations, suppressed T-cell quantities/function, and the development of patient’s immunosuppressive/inflammatory endotypes. We will primarily focus on how MDSC expansion evolves over time in surgical sepsis patients who do or do not rapidly recover; how myelopoiesis is regulated transcriptionally and epigenetically in the bone marrow of trauma patients who are at high risk of developing sepsis. There are four specific aims: Aim 1. To test the hypothesis that perpetuation of host MDSCs after acute surgical sepsis drives poor long-term clinical outcomes in surgical sepsis, including but not limited to increased secondary infections. Aim 2. To test the hypothesis that failure to recover from surgical sepsis is driven by modifiable epigenetic alterations in circulating MDSCs that induce and prolong immunosuppressive endotypes. Aim 3. To identify the distinct immunosuppressive mechanisms of MDSCs from surgical sepsis patients over time, including immunometabolism, check-point inhibition, reactive oxygen and nitrogen production, and substrate availability. Aim 4. To test the hypothesis that in response to an initial inflammatory stimulus, the increased risk of developing surgical sepsis is secondary to immunosuppression driven by a preferential bone marrow hematopoietic stem cell (HSC) expansion of MDSCs transcriptionally and epigenetically. This will be analyzed in severe blunt trauma patients at high risk for post-injury sepsis who manifest early changes in bone marrow progenitors and expansion of immunosuppressive MDSCs. Using the established clinical infrastructure of the Sepsis and Critical Illness Research Center (SCIRC), a team science approach will be employed with collaborating PI’s coming from multiple clinical and basic science disciplines. Ongoing regular biweekly meetings currently address program, resource and professional development, as well as time and effort allocation and conflict resolution.