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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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Experimental design for detecting host transcriptional responses to different Mtb W-Beijing strains.Genetic diversity of W-Beijing family strains, as revealed by SNPs-based genotyping (see our recent work [16] for details). In brief, 48 SNPs were characterized by sequencing 22 genes (being involved in DNA repair, replication, and recombination) in 58 W-Beijing isolates plus one non-W-Beijing isolate (Myc2). Each node represents one genotype (the same SNPs profile), with the node area proportional to the population size (the number of W-Beijing isolates in it was indicated on the left). Strains from the corresponding node used for the THP-1 infection in this study (e.g., R1.4 from Bmyc10) were indicated on the right. Lab strain H37Rv, which was also recruited for the THP-1 infection, was not shown here.
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pone-0038367-g001: Experimental design for detecting host transcriptional responses to different Mtb W-Beijing strains.Genetic diversity of W-Beijing family strains, as revealed by SNPs-based genotyping (see our recent work [16] for details). In brief, 48 SNPs were characterized by sequencing 22 genes (being involved in DNA repair, replication, and recombination) in 58 W-Beijing isolates plus one non-W-Beijing isolate (Myc2). Each node represents one genotype (the same SNPs profile), with the node area proportional to the population size (the number of W-Beijing isolates in it was indicated on the left). Strains from the corresponding node used for the THP-1 infection in this study (e.g., R1.4 from Bmyc10) were indicated on the right. Lab strain H37Rv, which was also recruited for the THP-1 infection, was not shown here.

Mentions: Here we aimed at exploring host macrophage response to Mtb W-Beijing on a genome-wide scale using gene expression profiling. Transcriptome profiling has been widely used to gain insights into host-mycobacteria interactions in various contexts [11]. In this study, we used the human macrophage-like THP-1 cell line as a model of innate immune cell because it allows to minimize the influence of host heterogeneity as compared to human blood donor-derived primary macrophages [12]. In addition to the reference laboratory strain H37Rv, a total of eleven Mtb strains representing six sublineages of the W-Beijing family (Figure 1) were used to infect host cells, and were subsequently profiled using whole-genome expression arrays. Through detailed data mining, we found transcriptome responses of the host were largely similar, irrespective of the Mtb W-Beijing subgroups tested, although it could not be excluded that there were minor differences between different strains. Accordingly, a core response gene signature was recognized (THP1r2Mtb-induced signature). Based on this gene signature and cross-study comparisons, we were able to identify several putative immunity-related, and more particularly interferon-related, transcription factors that might regulate the core host transcriptional response. We were also able to show the clinical relevance of such core responses with those observed in active pulmonary tuberculosis patients [13], which appears to be tuberculosis specific when compared to patients from other inflammatory diseases and pathological conditions [14], [15]. These results provide new insights into the host-pathogen cross-talk in Mtb infections.


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)

Experimental design for detecting host transcriptional responses to different Mtb W-Beijing strains.Genetic diversity of W-Beijing family strains, as revealed by SNPs-based genotyping (see our recent work [16] for details). In brief, 48 SNPs were characterized by sequencing 22 genes (being involved in DNA repair, replication, and recombination) in 58 W-Beijing isolates plus one non-W-Beijing isolate (Myc2). Each node represents one genotype (the same SNPs profile), with the node area proportional to the population size (the number of W-Beijing isolates in it was indicated on the left). Strains from the corresponding node used for the THP-1 infection in this study (e.g., R1.4 from Bmyc10) were indicated on the right. Lab strain H37Rv, which was also recruited for the THP-1 infection, was not shown here.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366933&req=5

pone-0038367-g001: Experimental design for detecting host transcriptional responses to different Mtb W-Beijing strains.Genetic diversity of W-Beijing family strains, as revealed by SNPs-based genotyping (see our recent work [16] for details). In brief, 48 SNPs were characterized by sequencing 22 genes (being involved in DNA repair, replication, and recombination) in 58 W-Beijing isolates plus one non-W-Beijing isolate (Myc2). Each node represents one genotype (the same SNPs profile), with the node area proportional to the population size (the number of W-Beijing isolates in it was indicated on the left). Strains from the corresponding node used for the THP-1 infection in this study (e.g., R1.4 from Bmyc10) were indicated on the right. Lab strain H37Rv, which was also recruited for the THP-1 infection, was not shown here.
Mentions: Here we aimed at exploring host macrophage response to Mtb W-Beijing on a genome-wide scale using gene expression profiling. Transcriptome profiling has been widely used to gain insights into host-mycobacteria interactions in various contexts [11]. In this study, we used the human macrophage-like THP-1 cell line as a model of innate immune cell because it allows to minimize the influence of host heterogeneity as compared to human blood donor-derived primary macrophages [12]. In addition to the reference laboratory strain H37Rv, a total of eleven Mtb strains representing six sublineages of the W-Beijing family (Figure 1) were used to infect host cells, and were subsequently profiled using whole-genome expression arrays. Through detailed data mining, we found transcriptome responses of the host were largely similar, irrespective of the Mtb W-Beijing subgroups tested, although it could not be excluded that there were minor differences between different strains. Accordingly, a core response gene signature was recognized (THP1r2Mtb-induced signature). Based on this gene signature and cross-study comparisons, we were able to identify several putative immunity-related, and more particularly interferon-related, transcription factors that might regulate the core host transcriptional response. We were also able to show the clinical relevance of such core responses with those observed in active pulmonary tuberculosis patients [13], which appears to be tuberculosis specific when compared to patients from other inflammatory diseases and pathological conditions [14], [15]. These results provide new insights into the host-pathogen cross-talk in Mtb infections.

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