A derived network-based interferon-related signature of human macrophages responding to Mycobacterium tuberculosis.
Network analysis of transcriptional signature typically relies on direct interaction between two highly expressed genes. However, this approach misses indirect and biological relevant interactions through a third factor (hub). Here we determine whether a hub-based network analysis can select an improved signature subset that correlates with a biological change in a stronger manner than the original signature. We have previously reported an interferon-related transcriptional signature (THP1r2Mtb-induced) from Mycobacterium tuberculosis (M. tb)-infected THP-1 human macrophage. We selected hub-connected THP1r2Mtb-induced genes into the refined network signature TMtb-iNet and grouped the excluded genes into the excluded signature TMtb-iEx. TMtb-iNet retained the enrichment of binding sites of interferon-related transcription factors and contained relatively more interferon-related interacting genes when compared to THP1r2Mtb-induced signature. TMtb-iNet correlated as strongly as THP1r2Mtb-induced signature on a public transcriptional dataset of patients with pulmonary tuberculosis (PTB). TMtb-iNet correlated more strongly in CD4(+) and CD8(+) T cells from PTB patients than THP1r2Mtb-induced signature and TMtb-iEx. When TMtb-iNet was applied to data during clinical therapy of tuberculosis, it resulted in the most pronounced response and the weakest correlation. Correlation on dataset from patients with AIDS or malaria was stronger for TMtb-iNet, indicating an involvement of TMtb-iNet in these chronic human infections. Collectively, the significance of this work is twofold: (1) we disseminate a hub-based approach in generating a biologically meaningful and clinically useful signature; (2) using this approach we introduce a new network-based signature and demonstrate its promising applications in understanding host responses to infections.
Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai 201508, China ; Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China ; State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, China.
Kang
K
Wu
State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, China.
Hai
H
Fang
Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai 201508, China.
Liang-Dong
LD
Lyu
Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai 201508, China ; Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Douglas B
DB
Lowrie
Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai 201508, China ; Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Ka-Wing
KW
Wong
Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Shanghai 201508, China ; Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Xiao-Yong
XY
Fan
D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007372:Interferons / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology
D014157:Transcription Factors; D007372:Interferons