Divergent chromatin remodeling trajectories in CD66b⁺ MDSCs distinguishes recovery from chronic critical illness after sepsis

Sepsis remains a leading cause of morbidity and mortality worldwide, with survivors often following divergent trajectories: rapid recovery (RAP) or progression to chronic critical illness (CCI). CCI is characterized by persistent organ dysfunction, recurrent infections, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs), which expand in number after sepsis, are implicated in this maladaptive state, yet their epigenetic regulation remains poorly understood. Here, we applied an Omni-ATAC protocol optimized to profile chromatin accessibility in CD66b+ MDSCs from healthy participants (HPs) and sepsis patients across time points (day 4, day 14-21, and 6 months) and clinical outcomes (RAP, CCI, and Deceased). Dimensionality reduction analyses of genome-wide chromatin accessibility showed clear separation of sepsis and HP samples. Furthermore, these analyses revealed distinct trajectories post-sepsis diagnosis: RAP samples progressively regained HP-like chromatin states, whereas CCI samples remained epigenetically "locked" in aberrant states. Differential accessibility analysis identified thousands of promoter regions with altered accessibility, including immune checkpoint and inflammatory genes (e.g., ARG1, CD274, S100A8/9). Pathway analyses predicted global suppression of immune, metabolic, and chromatin remodeling programs in CCI, contrasting with restoration in RAP. These findings from patient-derived CD66b+ MDSCs suggest that epigenetic chromatin remodeling underlies divergent recovery trajectories and highlight chromatin-modifying pathways as potential therapeutic targets to restore immune competence in sepsis patients with CCI.