Abstract
To study the dysregulated host immune response to infection in sepsis, gene expression profiles from the Gene Expression Omnibus (GEO) datasets GSE54514, GSE57065, GSE64456, GSE95233, GSE66099 and GSE72829 were selected. From the Kyoto Encyclopedia of Genes and Genomes (KEGG) immune system pathways, 998 unique genes were selected, and genes were classified as follows based on gene annotation from KEGG, Gene Ontology, and Reactome: adaptive immunity, antigen presentation, cytokines and chemokines, complement, hematopoiesis, innate immunity, leukocyte migration, NK cell activity, platelet activity, and signaling. After correlation matrix formation, correlation coefficient of 0.8 was selected for network generation and network analysis. Total transcriptome was analyzed for differentially expressed genes (DEG), followed by gene set enrichment analysis. The network topological structure revealed that adaptive immunity tended to form a prominent and isolated cluster in sepsis. Common genes within the cluster from the 6 datasets included CD247, CD8A, ITK, LAT, and LCK. The clustering coefficient and modularity parameters were increased in 5/6 and 4/6 datasets in the sepsis group that seemed to be associated with functional aspect of the network. GSE95233 revealed that the nonsurvivor group showed a prominent and isolated adaptive immunity cluster, whereas the survivor group had isolated complement-coagulation and platelet-related clusters. T cell receptor signaling (TCR) pathway and antigen processing and presentation pathway were down-regulated in 5/6 and 4/6 datasets, respectively. Complement and coagulation, Fc gamma, epsilon related signaling pathways were up-regulated in 5/6 datasets. Altogether, network and gene set enrichment analysis showed that adaptive-immunity-related genes along with TCR pathway were down-regulated and isolated from immune the network that seemed to be associated with unfavorable prognosis. Prominence of platelet and complement-coagulation-related genes in the immune network was associated with survival in sepsis. Complement-coagulation pathway was up-regulated in the sepsis group that was associated with favorable prognosis. Network and gene set enrichment analysis supported elucidation of sepsis pathogenesis.
Highlights
Sepsis is defined as a documented infection with immune dysfunction or dysregulated host response with organ dysfunction [1,2,3]
We found that complement and coagulation cascade pathway and Fc epsilon RI signaling and Fc gamma R-mediated phagocytosis pathways were up-regulated in 2/3 of datasets from adult patients and in 3/3 of those from pediatric patients
Adaptive immunity was associated with unfavorable prognosis in sepsis group
Summary
Sepsis is defined as a documented infection with immune dysfunction or dysregulated host response with organ dysfunction [1,2,3]. Sepsis cases are composed of a heterogeneous subset of patients with various biological and clinical characteristics, including age, medication, underlying disease, causative microbes, and microbes with different antibiotic resistances [4, 5] These features might act as confounding factors or cause in patients various immune responses or immune dysfunction. Immune dysfunction or dysregulated host response in sepsis is associated with defective antigen presentation, defective adaptive immunity, defective NK cell activity, decreased immunoglobulin levels, neutrophil abnormalities, hypercytokinemia, complement consumption, and defective bacterial removal [6,7,8] These features occur in the time course of disease by themselves or as a combination of more than two features. Up- or down-regulated genes and pathways related to sepsis support the understanding of sepsis [11,12,13]
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