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

IF 2.7 3区医学 Q2 CRITICAL CARE MEDICINE

SHOCK Pub Date : 2026-09-01 Epub Date: 2026-08-07 DOI:10.1097/SHK.0000000000002852

Jinwei Dai, Nianzhe Sun, Lina Zhang, Zhaoxin Qian, Zhihong Zuo

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引用次数: 0

Abstract

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.

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血友病信息遗传和转录组学分析确定IL-7和Vegfa是免疫抑制性脓毒症内型的驱动因素。

背景：脓毒症表现出明显的生物学异质性，然而将宿主免疫介质与临床相关内型联系起来的因果途径仍然不明确，特别是在病原体特异性背景下。方法：我们应用孟德尔随机化（MR）研究循环免疫介质对血友病血友病风险的因果影响，确定白细胞介素-7 （IL-7）和血管内皮生长因子A （VEGFA）为推定的因果因素。为了阐明这些遗传关联背后的生物学背景，我们将病原体相关基因集与来自大型脓毒症队列（GSE185263）的大量血液转录组数据结合起来。使用单样本基因集富集分析和途径响应基因（PROGENy）来推断途径活性，随后与先前报道的脓毒症内型相一致。结果：血液病通知的转录评分捕获了由TGFβ， TNFα/NFκB，缺氧和细胞死亡途径主导的独特信号传导结构，并伴有再生信号的抑制。这些途径活动与原始队列中描述的中性粒细胞主导的免疫抑制（NeutroSupp）内型最密切相关。虽然VEGFA的表达与VEGF和缺氧信号有很强的偶联，但通过Janus激酶信号转导器和转录活性激活器推断，il -7相关的免疫维持途径仅适度参与，与适应性免疫恢复受损一致。结论：通过整合遗传因果关系、转录组学和内型水平分析，我们的研究结果表明，IL-7和VEGFA通过不同的免疫内皮轴参与脓毒症风险，这些轴聚集在免疫抑制性脓毒症内型上。这项工作为解释临床相关败血症表型中的遗传关联提供了一个病原体知情框架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SHOCK 医学-外科

CiteScore

6.20

自引率

3.20%

发文量

199

审稿时长

1 months

期刊介绍： SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.