Effect of phthiocerol dimycocerosate deficiency on the transcriptional response of human macrophages to Mycobacterium tuberculosis.
ABSTRACT The control of mycobacterial infections is dependent on the finely tuned synergism between the innate and adaptive immune responses. The macrophage is the major host cell for Mycobacterium tuberculosis and the degree of virulence of mycobacteria may influence the initial macrophage response to infection. The cell wall molecule, phthiocerol dimycocerosate (DIM), is an important virulence factor that influences the early growth of M. tuberculosis in the lungs. To explore the basis for this effect we have compared the early gene response of human THP-1 macrophages to infection with virulent M. tuberculosis and the DIM-deficient DeltafadD26 M. tuberculosis strain using microarrays. Detailed analysis revealed a common core of macrophage genes, which were rapidly induced following infection with both strains, and deficiency of DIM had no significant effect on this initial macrophage transcriptional responses. In addition to chemokines and pro-inflammatory cytokines, the early response genes included components of the Toll-like receptor signalling, antigen presentation and apoptotic pathways, interferon response genes, cell surface receptors and their ligands, including TNF-related apoptosis inducing ligand (TRAIL) and CD40, and other novel genes. Therefore, although fadD26 deficiency is responsible for the early attenuation of the growth of M. tuberculosis in vivo, this effect is not associated with differences in the initial macrophage transcriptional response.
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ABSTRACT: Latent tuberculosis represents a high-risk burden for one-third of the world population. Previous analysis of murine tuberculosis identified a novel transcriptional regulator encoded by Rv0348 that could control the establishment of persistent tuberculosis. Disruption of the Rv0348 gene from the genome of the virulent H37Rv strain of Mycobacterium tuberculosis revealed a global impact on the transcriptional profiles of 163 genes, including induction of the mammalian cell entry (mce1) operon and the repression of a significant number of genes involved in hypoxia and starvation responses. Nonetheless, gel shift assays did not reveal direct binding between Rv0348 and a set of regulated promoters, suggesting an indirect regulatory role. However, when expressed in Mycobacterium smegmatis, the Rv0348 transcripts were significantly responsive to different levels of hypoxia and the encoded protein was shown to regulate genes involved in hypoxia [e.g., Rv3130c (tgs1)] and intracellular survival (e.g., mce1), among other genes. Interestingly, the colonization level of the DeltamosR mutant strain was significantly lower than that of the wild-type strain of M. tuberculosis, suggesting its attenuation in the murine model of tuberculosis. Taken together, our analyses indicated that the Rv0348 gene encodes a novel transcriptional factor that regulates several operons involved in mycobacterial survival, especially during hypoxia; hence, we propose that Rv0348 be renamed mosR for regulator of mycobacterial operons of survival.Journal of bacteriology 08/2009; 191(19):5941-52. · 3.94 Impact Factor
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ABSTRACT: Mycobacterium abscessus, a relative of Koch's bacillus (the bacterium that causes tuberculosis), has recently emerged as the cause of an increasing number of both community- and hospital-acquired infections in humans; it also constitutes a serious threat for cystic fibrosis patients. This situation is worsened by its exceptionally high natural and acquired antibiotic resistance that complicates treatment. Although a rapid grower, it shares some traits with Koch's bacillus, including the ability to induce a persistent lung disease associated with caseous lesions, a landmark of Mycobacterium tuberculosis infection. Its genome sequence and microarrays are now available, and efficient genetic tools have recently been developed. Here we consider the various advantages of using this species as an experimental model to study tuberculosis and other related mycobacterial diseases.Trends in Microbiology 03/2010; 18(3):117-23. · 8.43 Impact Factor
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ABSTRACT: The resurgence of tuberculosis (TB) and emergence of multidrug-resistant TB (MDR-TB) are significant obstacles to stop TB treatment. Capreomycin (CPM) is regarded as an ideal second-line treatment for TB as well as for MDR-TB. However, the inexorable emergence of capreomycin resistant TB cases accentuates the urgent need for more detailed characterization of CPM targets. Most of these are single gene mutation, such as those involved in the complex formation of ribosomal 30S initiation, inhibit protein synthesis, affect 50S ribosomal protein L10, control transcription and translation of operon rpIJL-rpoBC. A new paradigm integrating gene, small metabolites, protein and underlying signaling pathway to shed light on the physiology, pathogenesis, and network of pathogen response is emerging. This model holds great promise to unravel the intricacy of drug action. However, to our knowledge, no such work regarding Mycobacterium tuberculosis response to capreomycin exposure was ever reported. We employed the data mining to construct an interaction topology of M. tuberculosis genes response to capreomycin. Most valuable genes were summarized for further experimental validation based on this topology. Dampening the virulence factors and respiratory of M. tuberculosis might be the new targets of CPM beyond Rv1364c, pe_pgrs38, pe_pgrs51 which are the salient nodes of the network and represent most promising new capreomycin targets meriting further exploration. This work will facilitate further investigation of capreomycin targets against M. tuberculosis and be conducive to novel TB drug discovery.Journal of Cellular Biochemistry 06/2011; 112(10):2716-20. · 3.06 Impact Factor