Biomarkers of pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis through single-cell transcriptomics

Jie Shen, Yunyan He, Hong Zheng, Jianwen Xiao, Fu Li, Keke Chen, Biyun Guo, Yulei He, Lin Liu, Zhi Lin, Dan Wang, Leping Liu, Shengfeng Wang, Wen Zhou, Yingchi Zhang, Jian Wei, Yunchu Wang, Rong Hu, Daolin Tang, Dao Wang () and Minghua Yang ()
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Jie Shen: Central South University
Yunyan He: The First Affiliated Hospital of Guangxi Medical University
Hong Zheng: Central South University
Jianwen Xiao: Children Hospital of Chongqing Medical University
Fu Li: Children’s Hospital Affiliated to Shandong University and Jinan Children’s Hospital
Keke Chen: Children’s Medical Center of Hunan Provincial People’s Hospital of the First-Affiliated Hospital
Biyun Guo: The First Affiliated Hospital of Xiamen University
Yulei He: University of Electronic Science and Technology of China
Lin Liu: Central South University
Zhi Lin: Central South University
Dan Wang: Central South University
Leping Liu: Central South University
Shengfeng Wang: Central South University
Wen Zhou: Central South University
Yingchi Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Jian Wei: Xiangxi Autonomous Prefecture People’s Hospital
Yunchu Wang: Liuyang people’s hospital
Rong Hu: The First People’s Hospital of Changde City
Daolin Tang: UT Southwestern Medical Center
Dao Wang: The First Affiliated Hospital of Zhengzhou University
Minghua Yang: Central South University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a fatal hyperinflammatory disorder distinct from self-limiting EBV-induced infectious mononucleosis (IM). However, the immunological mechanisms underlying the divergence between benign EBV infection and fulminant HLH—particularly in the absence of inherited immunodeficiency—remains unclear, and systematic comparisons of immune landscapes across EBV-associated disease spectra are lacking. In this study, by enrolling children with IM and healthy volunteers as controls, we utilize single-cell RNA sequencing to identify unique immunological characteristics of EBV-HLH. Our analysis indicates that patients with EBV-HLH exhibite widespread activation of NF-κB signaling pathway. Furthermore, excessive cytokine secretion by T and NK cells is observed, along with a shift in monocyte differentiation towards an inflammatory phenotype, and the aggregation of IDO1+ monocytes. Metabolic pathway analysis reveals that L-kynurenine, a downstream metabolite of IDO1, is specifically elevated in EBV-HLH and mediates the production of multiple pro-inflammatory cytokines. Collectively, our study maps the immune landscape in pediatric EBV-HLH at single-cell resolution, uncovering potential role of IDO1+ monocytes and L-kynurenine as biomarkers.

Date: 2025
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DOI: 10.1038/s41467-025-62090-5

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