Multi-cohort transcriptomics and donor-aware single-cell analyses prioritize S100A8 within an emergency-myeloid, HLA-DR-low state in sepsis
- 1The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
- 2Bengbu Medical University, Bengbu, Anhui, China.
- 3Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, Anhui, China.
Abstract
Sepsis is heterogeneous, and transcripts that distinguish sepsis from health may lack clinical specificity. We tested whether S100A8 is reproducibly associated with sepsis and maps to a donor-aware myeloid state defined independently of S100A8. A discovery whole-blood cohort was analyzed on the log2 robust multi-array average scale using maximum-probe aggregation, limma, weighted gene co-expression network analysis (WGCNA), and leakage-controlled feature prioritization. The analysis identified 1,508 differentially expressed genes; 265 overlapped the strongest sepsis-positive WGCNA module. The network retained all 802 samples and 11,719 genes; the black-module eigengene correlated with sepsis status (r = 0.409; false-discovery rate 3.72 × 10 − 33), and S100A8 belonged to this module (module membership 0.700). S100A8 was upregulated (log2 fold change 1.87; false-discovery rate 2.15 × 10 − 171). Discrimination against clinical comparators was contrast dependent, and outcome analyses did not support a stable prognostic association. Donor-level monocyte pseudo-bulk analysis supported increased S100A8 and decreased HLA-DRA but included only two control and four sepsis donors. Across single-cell datasets, S100A8 tracked an emergency-myeloid program and inversely tracked antigen presentation. In THP-1 cells, S100A8 knockdown attenuated lipopolysaccharide-associated reductions in CD74 and HLA-DRα. Triptolide retained a similar NF-κB phosphorylation effect after S100A8 knockdown, providing no evidence that this effect required S100A8. S100A8 is therefore prioritized as a marker of a sepsis-associated emergency-myeloid, HLA-DR-low state, not as an established diagnostic, prognostic, direct drug-binding, or therapeutic target.
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BibTeX
@article{zhang2026multicohort,
title = {{Multi-cohort transcriptomics and donor-aware single-cell analyses prioritize S100A8 within an emergency-myeloid, HLA-DR-low state in sepsis}},
author = {Changlong Zhang and Qianqian Cui and Qiyun Wu and Wei Tang and Lei Zhang and Liang Chu},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359578},
url = {https://doi.org/10.1371/journal.pone.0359578},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-cohort transcriptomics and donor-aware single-cell analyses prioritize S100A8 within an emergency-myeloid, HLA-DR-low state in sepsis
AU - Changlong Zhang
AU - Qianqian Cui
AU - Qiyun Wu
AU - Wei Tang
AU - Lei Zhang
AU - Liang Chu
PY - 2026
DA - 2026/10/21
JO - PLOS One
DO - 10.1371/journal.pone.0359578
UR - https://doi.org/10.1371/journal.pone.0359578
AB - Sepsis is heterogeneous, and transcripts that distinguish sepsis from health may lack clinical specificity. We tested whether S100A8 is reproducibly associated with sepsis and maps to a donor-aware myeloid state defined independently of S100A8. A discovery whole-blood cohort was analyzed on the log2 robust multi-array average scale using maximum-probe aggregation, limma, weighted gene co-expression network analysis (WGCNA), and leakage-controlled feature prioritization. The analysis identified 1,508 differentially expressed genes; 265 overlapped the strongest sepsis-positive WGCNA module. The network retained all 802 samples and 11,719 genes; the black-module eigengene correlated with sepsis status (r = 0.409; false-discovery rate 3.72 × 10 − 33), and S100A8 belonged to this module (module membership 0.700). S100A8 was upregulated (log2 fold change 1.87; false-discovery rate 2.15 × 10 − 171). Discrimination against clinical comparators was contrast dependent, and outcome analyses did not support a stable prognostic association. Donor-level monocyte pseudo-bulk analysis supported increased S100A8 and decreased HLA-DRA but included only two control and four sepsis donors. Across single-cell datasets, S100A8 tracked an emergency-myeloid program and inversely tracked antigen presentation. In THP-1 cells, S100A8 knockdown attenuated lipopolysaccharide-associated reductions in CD74 and HLA-DRα. Triptolide retained a similar NF-κB phosphorylation effect after S100A8 knockdown, providing no evidence that this effect required S100A8. S100A8 is therefore prioritized as a marker of a sepsis-associated emergency-myeloid, HLA-DR-low state, not as an established diagnostic, prognostic, direct drug-binding, or therapeutic target.
SN - 1932-6203
ER -