Immune gene expression networks in sepsis: A network biology approach

PLoS One. 2021 Mar 5;16(3):e0247669. doi: 10.1371/journal.pone.0247669. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Antigen Presentation / genetics
  • CD3 Complex / genetics
  • CD3 Complex / immunology
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology
  • Complement System Proteins / genetics
  • Complement System Proteins / immunology
  • Computational Biology / methods
  • Datasets as Topic
  • Gene Expression Profiling
  • Gene Expression Regulation / immunology*
  • Gene Ontology
  • Gene Regulatory Networks / immunology*
  • Humans
  • Immunity, Innate
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Molecular Sequence Annotation
  • Prognosis
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Sepsis / diagnosis
  • Sepsis / genetics*
  • Sepsis / immunology
  • Sepsis / mortality
  • Signal Transduction
  • Survival Analysis
  • Transcriptome / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • CD3 Complex
  • CD3 antigen, zeta chain
  • CD8 Antigens
  • CD8 antigen, alpha chain
  • LAT protein, human
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Complement System Proteins
  • Protein-Tyrosine Kinases
  • LCK protein, human
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • emt protein-tyrosine kinase

Grants and funding

This study was funded by Seoul St. Mary's Hospital, The Catholic University of Korea to promote scientific work. This hosptial is affiliated to The Catholic University of Korea, Seoul, Korea. Six of the authors work at University. As following authors work at the hospital, they received a salary from Incheon St Mary's Hospital, which is affiliated to The Catholic University of Korea, Seoul, Korea.: Kyung Soo Kim, Dong Wook Jekarl, Myungshin Kim, Yonggoo Kim, Jaeeun Yoo and Seungok Lee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.