Chinese researchers have used multi-omic profiling to comprehensively map the immune landscape of sepsis, which could lead to new precision treatments.
The findings, in Nature Immunology, revealed both shared and divergent immune responses shaped by the anatomical site of infection and the patient’s age.
It also identified distinct subsets of immune cells with unique functional states and molecular profiles, which could potentially be used as biomarkers or targets for precision immunotherapy.
“Our study provides a comprehensive immune landscape of sepsis across infection sources and age groups, highlighting critical immune subsets as potential biomarkers and therapeutic targets,” reported Qian Je, PhD, from First Affiliated Hospital of Chongqing Medical University, and colleagues.
“These findings may inform the development of clinically applicable assays for patient stratification and prognosis and offer a framework for precision immunomodulatory strategies in sepsis care.”
Sepsis involves life-threatening organ dysfunction in response to infection and accounts for nearly a fifth of deaths worldwide.
Clinical decisions are often based on the presumed site of infection, so understanding distinct immune features relating to these is a critical part of precise and individualized treatment strategies.
But while the anatomical source of infection is known to be a major determinant of outcomes, how distinct sites shape immunity remains unclear.
To investigate further, Je and co-workers used a multi-omic approach that integrated single-cell transcriptomics—to enable high-resolution analysis of cellular differences—with single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing, and plasma proteomics.
These techniques were used to analyze peripheral blood mononuclear cells and serum samples from 281 adult and pediatric patients with sepsis and control individuals.
To validate their findings, the team then integrated external single-cell and transcriptomic datasets, confirmed key subsets using flow cytometry in independent cohorts, and obtained mechanistic insights from CD4+ T cell-specific Nr4a2 overexpression and knockout mouse models.
Results showed that an NR4A2-expressing central memory CD4+ T cell subset enriched in abdominal, pulmonary, and skin sepsis exhibited an exhaustion phenotype and was associated with poor sepsis prognosis, suggesting that NR4A2 may act as a central regulator of T cell dysfunction in the condition.
While Nr4a2 loss improved survival, overexpression worsened it.
Proinflammatory CD8+ T, natural killer and natural killer T subsets expressing CCL4, CCL3 and tumor necrosis factor expanded in cases of adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14+ monocytes.
Plasma proteomics revealed shared mediators that included interleukin-6 and EN-RAGE across anatomical sites and different age groups.
Ye and team reported: “Collectively, these analyses delineate shared and source-specific immune programs in adult and pediatric sepsis, providing a framework for stratification, biomarker development, and precision immunotherapeutic strategies tailored to age and infection source.”
