Loftus, T. J. | Search bioRxiv

bioRxiv2026

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

Sepsis survivors exhibit divergent clinical trajectories, including rapid recovery (RAP) or progression to chronic critical illness (CCI), yet how these outcomes are linked to epigenetic repression remains poorly defined. Here, we applied an optimized Omni-ATAC approach to profile chromatin accessibility in CD66b myeloid-derived suppressor cells (MDSCs) from healthy participants and longitudinally sampled sepsis cohorts stratified by outcome. RAP samples progressively restored healthy chromatin states, whereas CCI samples remained epigenetically fixed in aberrant configurations. Chromatin remodeling exhibited strong pathway specificity: promoters associated with MHC class II antigen presentation were coordinately repressed in CCI, while MHC class I antigen processing and presentation machinery remained preserved. Genome-wide analyses revealed extensive promoter remodeling during recovery in RAP, including immune regulatory loci such as ARG1, CD274, and S100A8/A9, contrasted with broad suppression of immune, metabolic, and chromatin regulatory programs in CCI. These findings define divergent epigenetic trajectories in post-sepsis MDSCs and implicate selective failure of antigen presentation as a mechanism of sepsis-induced immunoparalysis in CCI.

immunology↗

bioRxiv2024

Determining potential immunomodulatory drug efficacy in sepsis using ELISpot

PurposeThis study evaluated the ability of ELISpot to identify immuno-modulatory drug therapies for their potential efficacy in patients with sepsis. MethodsELISpot was performed using diluted whole blood from 61 septic patients and 48 healthy matched controls. Innate and adaptive immunity were evaluated by ex vivo stimulated production of TNF- and IFN-{gamma} respectively. Potential drug efficacy was determined by the drugs effects to increase or decrease the number of cytokine-producing cells and amount of cytokine produced per cell as determined by spot size and intensity. The corticosteroid dexamethasone was evaluated for its ability to down modulate TNF- and IFN-{gamma} production. The TLR7/8 agonist resiquimod (R848) and T-cell stimulants IL-7 and anti-PD-1 mAb were tested for their ability to enhance immune responses in sepsis. ResultsSpontaneous production of TNF- and IFN-{gamma} varied among healthy subjects and septic patients. LPS or resiquimod stimulation increased total TNF- production in septic patients by 1,648% and 1,929% respectively. Conversely, dexamethasone diminished the responses to LPS or resiquimod by 71% and 61% respectively. IL-7, but not anti-PD-1 mAb markedly increased IFN-{gamma} production in both healthy subjects (127%) and septic patients (79%). Dexamethasone also reduced anti-CD3/CD28 mAb stimulated IFN-{gamma} production by 54%; while IL-7 ameliorated dexamethasone-induced suppression. IL-7 significantly enhanced lymphocyte function in over 90% of septic patients. ConclusionELISpot can reveal host immune response patterns and the effects of drugs to selectively down- or up-regulate patient immunity. Furthermore, the ability of ELISpot to detect the effect of specific immuno-modulatory drugs to independently regulate the innate and adaptive host response could enable precision-based immune drug therapies in sepsis.

immunology↗