SUMMARY The objective of this NIGMS MIRA/R35 proposal is to elucidate how sepsis induces chronically dysregulated myeloid-derived suppressor cell (MDSC) development, which promotes persistent immunosuppression with mounting mortality rates. The molecular basis of this newly identified chronic sepsis syndrome is unknown, but its clinical and economic effects are devastating. This proposal will develop a unifying concept to help explain delayed immunosuppression and to potentially treat this syndrome of unyielding innate and adaptive immunity incompetence. It will use an established and validated mouse model in order to develop the working model that persistent MDSC generation is a key contributor to late/chronic sepsis high morbidity and cumulative high mortality rate. Preliminary data support the notion that long non-coding RNA Hotairm1 directs S100A9 cytosol protein into the nucleus, after which it epigenetically generates chronic MDSC-dependent systemic immunosuppression. Our research plan is designed to identify the signaling and epigenetic reprogramming network of chronic MDSC generation, using validated biochemical and genetic tools. We expect that targeting Hotairm1 or S100A9 will overcome sepsis-induced chronic immunosuppression and improve late sepsis survival. Since targeting molecular mechanisms to treat sepsis has never succeeded in improving mortality after several decades, our enlightening a new syndrome, a new molecular pathway, and a new molecular targeting approach will substantially inform major gaps in understanding sepsis-associated life-threatening inflammation.