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An interferon-related signature in the transcriptional core response of human macrophages to Mycobacterium tuberculosis infection.

Wu K, Dong D, Fang H, Levillain F, Jin W, Mei J, Gicquel B, Du Y, Wang K, Gao Q, Neyrolles O, Zhang J - PLoS ONE (2012)

Bottom Line: Analysis of the putative transcription factor binding sites in promoter regions of genes in this signature identified several key regulators, namely STATs, IRF-1, IRF-7, and Oct-1, commonly involved in interferon-related immune responses.The THP1r2Mtb-induced signature appeared to be highly relevant to the interferon-inducible signature recently reported in active pulmonary tuberculosis patients, as revealed by cross-signature and cross-module comparisons.Thus, our results provide an additional layer of information at the transcriptome level on mechanisms involved in host macrophage response to Mtb, which may also implicate the robustness of the cellular defense system that can effectively fight against genetic heterogeneity in this pathogen.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Genomics and Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT
The W-Beijing family of Mycobacterium tuberculosis (Mtb) strains is known for its high-prevalence and -virulence, as well as for its genetic diversity, as recently reported by our laboratories and others. However, little is known about how the immune system responds to these strains. To explore this issue, here we used reverse engineering and genome-wide expression profiling of human macrophage-like THP-1 cells infected by different Mtb strains of the W-Beijing family, as well as by the reference laboratory strain H37Rv. Detailed data mining revealed that host cell transcriptome responses to H37Rv and to different strains of the W-Beijing family are similar and overwhelmingly induced during Mtb infections, collectively typifying a robust gene expression signature ("THP1r2Mtb-induced signature"). Analysis of the putative transcription factor binding sites in promoter regions of genes in this signature identified several key regulators, namely STATs, IRF-1, IRF-7, and Oct-1, commonly involved in interferon-related immune responses. The THP1r2Mtb-induced signature appeared to be highly relevant to the interferon-inducible signature recently reported in active pulmonary tuberculosis patients, as revealed by cross-signature and cross-module comparisons. Further analysis of the publicly available transcriptome data from human patients showed that the signature appears to be relevant to active pulmonary tuberculosis patients and their clinical therapy, and be tuberculosis specific. Thus, our results provide an additional layer of information at the transcriptome level on mechanisms involved in host macrophage response to Mtb, which may also implicate the robustness of the cellular defense system that can effectively fight against genetic heterogeneity in this pathogen.

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Transcriptome classification of THP-1 cells to W-Beijing strains as well as the lab strain H37Rv.(A) Sample classification of THP-1 transcriptome responses to Mtb W-Beijing and H37Rv strains.W-Beijing strains from the same node (see Figure 1) were highlighted by the same color. For example, two CHN50 strains (CHN50.1 and CHN50.2) from node Bmyc26 were colored in black. (B) Component plane presentation integrated self-organizing map (CPP-SOM) of host transcriptomic responses to 11 different W-Beijing family strains as well as duplicated H37Rv (columns) at 3 time points (rows). Each presentation illustrates a sample- and time-specific transcriptome map, in which all the up-regulated (represented by neurons in red), down-regulated (represented by neurons in blue) and moderately regulated (represented by neurons in yellow and green) genes were well delineated. Linking these presentations allows visual-easy comparisons of transcriptome changes across time points and strains.
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pone-0038367-g002: Transcriptome classification of THP-1 cells to W-Beijing strains as well as the lab strain H37Rv.(A) Sample classification of THP-1 transcriptome responses to Mtb W-Beijing and H37Rv strains.W-Beijing strains from the same node (see Figure 1) were highlighted by the same color. For example, two CHN50 strains (CHN50.1 and CHN50.2) from node Bmyc26 were colored in black. (B) Component plane presentation integrated self-organizing map (CPP-SOM) of host transcriptomic responses to 11 different W-Beijing family strains as well as duplicated H37Rv (columns) at 3 time points (rows). Each presentation illustrates a sample- and time-specific transcriptome map, in which all the up-regulated (represented by neurons in red), down-regulated (represented by neurons in blue) and moderately regulated (represented by neurons in yellow and green) genes were well delineated. Linking these presentations allows visual-easy comparisons of transcriptome changes across time points and strains.

Mentions: In our recent work [16], we have used SNPs-based genotyping to characterize the genetic diversity of Mtb strains of the W-Beijing family. However, it remains unknown how host cells cope with the heterogeneity of these SNPs-genotyped strains. In an attempt to address this issue, we selected eleven W-Beijing strains from the six most representative sublineages (Figure 1), and these strains, in addition to H37Rv, were used to infect THP-1 host cells in a time-series setting. Using whole-genome expression arrays, we performed transcriptome profilings of THP-1 cells infected at three time points including early stage (4 h), intermediate stage (18 h), and late stage (48 h), as well as an uninfected sample (0 h) as a control. After array hybridization and data normalization, Absent-Present based filtering [12] was applied to select the most reliable probesets/transcripts. A total of 18,541 transcripts across the 39 infected samples (3 time points ×11 Mtb W-Beijing strains, 3 time points ×2 duplicated Mtb H37Rv strain, compared to the uninfected THP-1 cells as a control) remained and were subsequently used for unsupervised sample classifications. As shown in Figure 2A and Figure S1, samples were unambiguously classified into three groups, exactly corresponding to the infection time points, and independently of the strain genotype (i.e. H37Rv vs. W-Beijing, and among W-Beijing sublineages). When component plane presentations integrated self-organizing map (CPP-SOM) [17] were used to illustrate sample-specific transcriptome map, host cells infected by strains of different genotypes appeared to share similar global expression changes at each of all three infection time points (Figure 2B; see also pair-wise correlation coefficients in Figure S2). Moreover, the major changes were observed at the interval between 4 h and 18 h of infection, while little changes occurred thereafter. These observations suggested that host transcriptome responses do not rely on the genotype (i.e. sublineage) of the W-Beijing strains tested. To evaluate the possibility of whether the genetic diversity of the strains could instead be explained by function-specific differences in host cells, we also performed the sample classifications with the same parameters to Figure 2A but using genes only annotated to specific functional categories (i.e., immunity and defense from PANTHER classification system [18]). Like the results shown in Figure 2A, samples were again grouped together according to the infection duration, irrespective of the genotype of the strains (Figure S3). Further restriction using more specific immunity-related processes did not change the sample relationships (data not shown). In all, the host transcriptome responses induced by H37Rv and by different sublineages of Mtb W-Beijing strains are predominantly similar, and hardly broad differences as well as immune response-specific differences were detectable, even though we can not guarantee that minor differences would be observed if more biological replicates were involved. Although the small number of strains of each genotype used here may be insufficient to distinguish subtle genotype- and subgenotype-specific host cell responses, our results nevertheless suggested that a transcriptional core response of human macrophages to Mtb infection could be extracted from our data.


An interferon-related signature in the transcriptional core response of human macrophages to Mycobacterium tuberculosis infection.

Wu K, Dong D, Fang H, Levillain F, Jin W, Mei J, Gicquel B, Du Y, Wang K, Gao Q, Neyrolles O, Zhang J - PLoS ONE (2012)

Transcriptome classification of THP-1 cells to W-Beijing strains as well as the lab strain H37Rv.(A) Sample classification of THP-1 transcriptome responses to Mtb W-Beijing and H37Rv strains.W-Beijing strains from the same node (see Figure 1) were highlighted by the same color. For example, two CHN50 strains (CHN50.1 and CHN50.2) from node Bmyc26 were colored in black. (B) Component plane presentation integrated self-organizing map (CPP-SOM) of host transcriptomic responses to 11 different W-Beijing family strains as well as duplicated H37Rv (columns) at 3 time points (rows). Each presentation illustrates a sample- and time-specific transcriptome map, in which all the up-regulated (represented by neurons in red), down-regulated (represented by neurons in blue) and moderately regulated (represented by neurons in yellow and green) genes were well delineated. Linking these presentations allows visual-easy comparisons of transcriptome changes across time points and strains.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366933&req=5

pone-0038367-g002: Transcriptome classification of THP-1 cells to W-Beijing strains as well as the lab strain H37Rv.(A) Sample classification of THP-1 transcriptome responses to Mtb W-Beijing and H37Rv strains.W-Beijing strains from the same node (see Figure 1) were highlighted by the same color. For example, two CHN50 strains (CHN50.1 and CHN50.2) from node Bmyc26 were colored in black. (B) Component plane presentation integrated self-organizing map (CPP-SOM) of host transcriptomic responses to 11 different W-Beijing family strains as well as duplicated H37Rv (columns) at 3 time points (rows). Each presentation illustrates a sample- and time-specific transcriptome map, in which all the up-regulated (represented by neurons in red), down-regulated (represented by neurons in blue) and moderately regulated (represented by neurons in yellow and green) genes were well delineated. Linking these presentations allows visual-easy comparisons of transcriptome changes across time points and strains.
Mentions: In our recent work [16], we have used SNPs-based genotyping to characterize the genetic diversity of Mtb strains of the W-Beijing family. However, it remains unknown how host cells cope with the heterogeneity of these SNPs-genotyped strains. In an attempt to address this issue, we selected eleven W-Beijing strains from the six most representative sublineages (Figure 1), and these strains, in addition to H37Rv, were used to infect THP-1 host cells in a time-series setting. Using whole-genome expression arrays, we performed transcriptome profilings of THP-1 cells infected at three time points including early stage (4 h), intermediate stage (18 h), and late stage (48 h), as well as an uninfected sample (0 h) as a control. After array hybridization and data normalization, Absent-Present based filtering [12] was applied to select the most reliable probesets/transcripts. A total of 18,541 transcripts across the 39 infected samples (3 time points ×11 Mtb W-Beijing strains, 3 time points ×2 duplicated Mtb H37Rv strain, compared to the uninfected THP-1 cells as a control) remained and were subsequently used for unsupervised sample classifications. As shown in Figure 2A and Figure S1, samples were unambiguously classified into three groups, exactly corresponding to the infection time points, and independently of the strain genotype (i.e. H37Rv vs. W-Beijing, and among W-Beijing sublineages). When component plane presentations integrated self-organizing map (CPP-SOM) [17] were used to illustrate sample-specific transcriptome map, host cells infected by strains of different genotypes appeared to share similar global expression changes at each of all three infection time points (Figure 2B; see also pair-wise correlation coefficients in Figure S2). Moreover, the major changes were observed at the interval between 4 h and 18 h of infection, while little changes occurred thereafter. These observations suggested that host transcriptome responses do not rely on the genotype (i.e. sublineage) of the W-Beijing strains tested. To evaluate the possibility of whether the genetic diversity of the strains could instead be explained by function-specific differences in host cells, we also performed the sample classifications with the same parameters to Figure 2A but using genes only annotated to specific functional categories (i.e., immunity and defense from PANTHER classification system [18]). Like the results shown in Figure 2A, samples were again grouped together according to the infection duration, irrespective of the genotype of the strains (Figure S3). Further restriction using more specific immunity-related processes did not change the sample relationships (data not shown). In all, the host transcriptome responses induced by H37Rv and by different sublineages of Mtb W-Beijing strains are predominantly similar, and hardly broad differences as well as immune response-specific differences were detectable, even though we can not guarantee that minor differences would be observed if more biological replicates were involved. Although the small number of strains of each genotype used here may be insufficient to distinguish subtle genotype- and subgenotype-specific host cell responses, our results nevertheless suggested that a transcriptional core response of human macrophages to Mtb infection could be extracted from our data.

Bottom Line: Analysis of the putative transcription factor binding sites in promoter regions of genes in this signature identified several key regulators, namely STATs, IRF-1, IRF-7, and Oct-1, commonly involved in interferon-related immune responses.The THP1r2Mtb-induced signature appeared to be highly relevant to the interferon-inducible signature recently reported in active pulmonary tuberculosis patients, as revealed by cross-signature and cross-module comparisons.Thus, our results provide an additional layer of information at the transcriptome level on mechanisms involved in host macrophage response to Mtb, which may also implicate the robustness of the cellular defense system that can effectively fight against genetic heterogeneity in this pathogen.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Genomics and Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

ABSTRACT
The W-Beijing family of Mycobacterium tuberculosis (Mtb) strains is known for its high-prevalence and -virulence, as well as for its genetic diversity, as recently reported by our laboratories and others. However, little is known about how the immune system responds to these strains. To explore this issue, here we used reverse engineering and genome-wide expression profiling of human macrophage-like THP-1 cells infected by different Mtb strains of the W-Beijing family, as well as by the reference laboratory strain H37Rv. Detailed data mining revealed that host cell transcriptome responses to H37Rv and to different strains of the W-Beijing family are similar and overwhelmingly induced during Mtb infections, collectively typifying a robust gene expression signature ("THP1r2Mtb-induced signature"). Analysis of the putative transcription factor binding sites in promoter regions of genes in this signature identified several key regulators, namely STATs, IRF-1, IRF-7, and Oct-1, commonly involved in interferon-related immune responses. The THP1r2Mtb-induced signature appeared to be highly relevant to the interferon-inducible signature recently reported in active pulmonary tuberculosis patients, as revealed by cross-signature and cross-module comparisons. Further analysis of the publicly available transcriptome data from human patients showed that the signature appears to be relevant to active pulmonary tuberculosis patients and their clinical therapy, and be tuberculosis specific. Thus, our results provide an additional layer of information at the transcriptome level on mechanisms involved in host macrophage response to Mtb, which may also implicate the robustness of the cellular defense system that can effectively fight against genetic heterogeneity in this pathogen.

Show MeSH
Related in: MedlinePlus