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Gene expression models based on a reference laboratory strain are poor predictors of Mycobacterium tuberculosis complex transcriptional diversity.

ABSTRACT: Every year, species of the Mycobacterium tuberculosis complex (MTBC) kill more people than any other infectious disease caused by a single agent. As a consequence of its global distribution and parallel evolution with the human host the bacteria is not genetically homogeneous. The observed genetic heterogeneity has relevance at different phenotypic levels, from gene expression to epidemiological dynamics. However, current systems biology datasets have focused on the laboratory reference strain H37Rv. By using large expression datasets testing the role of almost two hundred transcription factors, we have constructed computational models to grab the expression dynamics of Mycobacterium tuberculosis H37Rv genes. However, we have found that many of those transcription factors are deleted or likely dysfunctional across strains of the MTBC. As a result, we failed to predict expression changes in strains with a different genetic background when compared with experimental data. These results highlight the importance of designing systems biology approaches that take into account the genetic diversity of tubercle bacilli, or any other pathogen, if we want to identify universal targets for vaccines, diagnostics and treatments.

SUBMITTER: Chiner-Oms A

PROVIDER: S-EPMC5830583 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Gene expression models based on a reference laboratory strain are poor predictors of Mycobacterium tuberculosis complex transcriptional diversity.

Chiner-Oms Álvaro Á González-Candelas Fernando F Comas Iñaki I

Scientific reports 20180228 1

Every year, species of the Mycobacterium tuberculosis complex (MTBC) kill more people than any other infectious disease caused by a single agent. As a consequence of its global distribution and parallel evolution with the human host the bacteria is not genetically homogeneous. The observed genetic heterogeneity has relevance at different phenotypic levels, from gene expression to epidemiological dynamics. However, current systems biology datasets have focused on the laboratory reference strain H ...[more]

PMID: 29491462

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Project description:BackgroundTuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb) remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by Mtb is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which Mtb strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon Mtb infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical Mtb strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB.ResultsIn spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551.In association with the differences in the macrophage responses to infection with the 2 Mtb strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878.ConclusionsIn association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a dysregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs.

Dataset Information

Gene expression models based on a reference laboratory strain are poor predictors of Mycobacterium tuberculosis complex transcriptional diversity.

Publications

Gene expression models based on a reference laboratory strain are poor predictors of Mycobacterium tuberculosis complex transcriptional diversity.

Similar Datasets

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