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A derived network-based interferon-related signature of human macrophages responding to Mycobacterium tuberculosis.

Wu K, Fang H, Lyu LD, Lowrie DB, Wong KW, Fan XY - Biomed Res Int (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

KEGG pathway analysis of TMtb-iNet and THP1r2Mtb-induced signature. KEGG pathways enriched in the two signatures (TMtb-iNet and THP1r2Mtb-induced) are displayed (FDR < 0.01). The refined genes in TMtb-iNet are listed on the right. Also see the gene list in Table S5.
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fig5: KEGG pathway analysis of TMtb-iNet and THP1r2Mtb-induced signature. KEGG pathways enriched in the two signatures (TMtb-iNet and THP1r2Mtb-induced) are displayed (FDR < 0.01). The refined genes in TMtb-iNet are listed on the right. Also see the gene list in Table S5.

Mentions: Figure 4(a) illustrates the layout of TMtb-iNet plus its cognate hubs with minimum degree 14 according to the subcellular localization of their gene products. In this layout, the expression changes of all genes were color-coded, showing the overwhelming induction (upregulation) especially at 18 h after M. tb infection (Figure 4(b)). TMtb-iNet significantly enriched the pathways of cytokine-cytokine receptor interaction, chemokine signaling, and NOD-like receptor signaling compared to THP1r2Mtb-induced signature (Figure 5 and Table S5). By contrast, TMtb-iEx did not enrich any pathway.


A derived network-based interferon-related signature of human macrophages responding to Mycobacterium tuberculosis.

Wu K, Fang H, Lyu LD, Lowrie DB, Wong KW, Fan XY - Biomed Res Int (2014)

KEGG pathway analysis of TMtb-iNet and THP1r2Mtb-induced signature. KEGG pathways enriched in the two signatures (TMtb-iNet and THP1r2Mtb-induced) are displayed (FDR < 0.01). The refined genes in TMtb-iNet are listed on the right. Also see the gene list in Table S5.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4209755&req=5

fig5: KEGG pathway analysis of TMtb-iNet and THP1r2Mtb-induced signature. KEGG pathways enriched in the two signatures (TMtb-iNet and THP1r2Mtb-induced) are displayed (FDR < 0.01). The refined genes in TMtb-iNet are listed on the right. Also see the gene list in Table S5.
Mentions: Figure 4(a) illustrates the layout of TMtb-iNet plus its cognate hubs with minimum degree 14 according to the subcellular localization of their gene products. In this layout, the expression changes of all genes were color-coded, showing the overwhelming induction (upregulation) especially at 18 h after M. tb infection (Figure 4(b)). TMtb-iNet significantly enriched the pathways of cytokine-cytokine receptor interaction, chemokine signaling, and NOD-like receptor signaling compared to THP1r2Mtb-induced signature (Figure 5 and Table S5). By contrast, TMtb-iEx did not enrich any pathway.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus