Haemophilus-Informed Genetic and Transcriptomic Analyses Identify IL-7 and Vegfa as Drivers of Immunosuppressive Sepsis Endotypes.

Background

Sepsis exhibits marked biological heterogeneity, yet the causal pathways linking host immune mediators to clinically relevant endotypes remain poorly defined, particularly in pathogen-specific contexts.

Methods

We applied Mendelian randomization (MR) to investigate the causal effects of circulating immune mediators on the risk of Haemophilus septicemia, identifying interleukin-7 (IL-7) and vascular endothelial growth factor A (VEGFA) as putative causal factors. To elucidate the biological context underlying these genetic associations, we integrated pathogen-informed gene sets with bulk blood transcriptomic data from a large sepsis cohort (GSE185263). Single-sample gene set enrichment analysis and Pathway responsive genes (PROGENy) were used to infer pathway activities, which were subsequently aligned with previously reported sepsis endotypes.

Results

A Haemophilus-informed transcriptional score captured a distinct signaling hierarchy dominated by TGFβ, TNFα/NFκB, hypoxia, and cell death pathways, accompanied by suppression of regenerative signaling. These pathway activities aligned most closely with the neutrophil-dominated, immunosuppressive (NeutroSupp) endotype described in the original cohort. While VEGFA expression showed strong coupling with VEGF and hypoxia signaling, IL-7-related immune maintenance pathways, inferred through Janus Kinase-signal transducer and activator of transcription activity, were only modestly engaged, consistent with impaired adaptive immune recovery.

Conclusions

By integrating genetic causality with transcriptomic and endotype-level analyses, our findings suggest that IL-7 and VEGFA contribute to sepsis risk through distinct immune-endothelial axes that converge on an immunosuppressive sepsis endotype. This work provides a pathogen-informed framework for interpreting genetic associations within clinically relevant sepsis phenotypes.