Cross-species transcriptomic comparison identifies a NKT cell dependent monocyte endotype that associates with immunosuppression and mortality in clinical sepsis

In sepsis, a dysregulated immune response to infection can lead to immunosuppression and opportunistic infections. Understanding immune endotypes related to post-sepsis immunosuppression may lead to improved therapeutic approaches. NKT cells are master regulators of post-sepsis immunosuppression and can be leveraged to dissect endotypes in vivo. Here, we start with murine models and then apply cross-species comparative transcriptomics to better define clinical endotypes associated with post-sepsis immunosuppression and mortality. We use NKT-cell deficient (Cd1d-/-) to define the innate immune transcriptome regulated by NKT cells in post-endotoxemia immunosuppression. We then compare these murine findings to the transcriptomic analysis of PBMC from septic shock patients at single-cell resolution. Three genes regulated by NKT cells in late endotoxemia–FPR1, FPR2, and MARCO–have increased expression across monocyte subpopulations in clinical septic shock. We previously emphasized the differences between the two monocyte states (MS1, MS3) expanded in sepsis; here, we identify a common signature shared by MS1 and MS3. In two independent clinical sepsis cohorts, FPR1 and FPR2 closely associate with Sepsis Response Signature 1 (SRS1), a previously defined transcriptional endotype predictive of immunosuppression and mortality. FPRs typically augment the antimicrobial response, but in sepsis these genes associate with immunosuppression in sepsis. In summary, we use cross species transcriptomics to identify NKT cell-regulated genes that are enriched across the monocyte subpopulations of clinical septic shock and associate with an immunosuppressed endotype.