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1
Veyrier, Frédéric, Battouli Saïd-Salim, and Marcel A. Behr. "Evolution of the Mycobacterial SigK Regulon." Journal of Bacteriology 190, no. 6 (2008): 1891–99. http://dx.doi.org/10.1128/jb.01452-07.
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ABSTRACT Previous studies have established that members of the Mycobacterium tuberculosis complex exhibit variable production of the antigenic proteins MPT70 and MPT83 due to mutations in their positive regulator, SigK (sigma factor K), and their negative regulator, RskA (regulator of sigma K). To further understand this highly specific SigK-controlled regulon, we have undertaken evolutionary studies to determine the presence of homologues of SigK-regulated genes in other organisms and to predict its transcriptional network. Evolutionary analysis indicates that the positive and negative regulators are conserved across many organisms, but that the genes under their control are variable. Moreover, the addition, loss, and movement of various genes in the mpt70/83 locus suggest that these genes are unlikely to be cotranscribed. To test predictions from sequence analysis, we have used promoter luciferase fusions and Northern blots to show that the majority of genes in this locus have their own promoters, of which a subset are SigK regulated (mpt83, dipZ, mpt70, and Rv0449c). Next, we have shown that the intracellular inducibility of mpt70 and mpt83 is a conserved property, shared between M. tuberculosis and Mycobacterium marinum. In addition, we have shown that SigK and RskA from an environmental mycobacterium isolate (M. gilvum PYR-GCK) complemented the regulatory activity of M. tuberculosis ΔsigK rskA. Together, our data indicate that the regulatory system SigK/RskA is conserved across the Mycobacterium genus, whereas the regulon under its control varies considerably across species.
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Malkhed, Vasavi, Bargavi Gudlur, Bhargavi Kondagari, Ramasree Dulapalli, and Uma Vuruputuri. "Study of interactions between Mycobacterium tuberculosis proteins: SigK and anti-SigK." Journal of Molecular Modeling 17, no. 5 (2010): 1109–19. http://dx.doi.org/10.1007/s00894-010-0792-7.
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Collins, Desmond M., Bronwyn Skou, Stefan White, et al. "Generation of Attenuated Mycobacterium bovis Strains by Signature-Tagged Mutagenesis for Discovery of Novel Vaccine Candidates." Infection and Immunity 73, no. 4 (2005): 2379–86. http://dx.doi.org/10.1128/iai.73.4.2379-2386.2005.
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ABSTRACT Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex, has a particularly wide host range and causes tuberculosis in most mammals, including humans. A signature tag mutagenesis approach, which employed illegitimate recombination and infection of guinea pigs, was applied to M. bovis to discover genes important for virulence and to find potential vaccine candidates. Fifteen attenuated mutants were identified, four of which produced no lesions when inoculated separately into guinea pigs. One of these four mutants had nine deleted genes including mmpL4 and sigK and, in guinea pigs with aerosol challenge, provided protection against tuberculosis at least equal to that of M. bovis BCG. Seven mutants had mutations near the esxA (esat-6) locus, and immunoblot analysis of these confirmed the essential role of other genes at this locus in the secretion of EsxA (ESAT-6) and EsxB (CFP10). Mutations in the eight other attenuated mutants were widely spread through the chromosome and included pks1, which is naturally inactivated in clinical strains of M. tuberculosis. Many genes identified were different from those found by signature tag mutagenesis of M. tuberculosis by use of a mouse infection model and illustrate how the use of different approaches enables identification of a wider range of attenuating mutants.
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Saïd-Salim, Battouli, Serge Mostowy, Arnold S. Kristof, and Marcel A. Behr. "Mutations in Mycobacterium tuberculosis Rv0444c, the gene encoding anti-SigK, explain high level expression of MPB70 and MPB83 in Mycobacterium bovis." Molecular Microbiology 62, no. 5 (2006): 1251–63. http://dx.doi.org/10.1111/j.1365-2958.2006.05455.x.
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Singh, Rakesh Kumar, Lav Kumar Jaiswal, Tanmayee Nayak, et al. "Expression, Purification, and In Silico Characterization of Mycobacterium smegmatis Alternative Sigma Factor SigB." Disease Markers 2022 (May 20, 2022): 1–11. http://dx.doi.org/10.1155/2022/7475704.
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Sigma factor B (SigB), an alternative sigma factor (ASF), is very similar to primary sigma factor SigA (σ70) but dispensable for growth in both Mycobacterium smegmatis (Msmeg) and Mycobacterium tuberculosis (Mtb). It is involved in general stress responses including heat, oxidative, surface, starvation stress, and macrophage infections. Despite having an extremely short half-life, SigB tends to operate downstream of at least three stress-responsive extra cytoplasmic function (ECF) sigma factors (SigH, SigE, SigL) and SigF involved in multiple signaling pathways. There is very little information available regarding the regulation of SigB sigma factor and its interacting protein partners. Hence, we cloned the SigB gene into pET28a vector and optimized its expression in three different strains of E. coli, viz., (BL21 (DE3), C41 (DE3), and CodonPlus (DE3)). We also optimized several other parameters for the expression of recombinant SigB including IPTG concentration, temperature, and time duration. We achieved the maximum expression of SigB at 25°C in the soluble fraction of the cell which was purified by affinity chromatography using Ni-NTA and further confirmed by Western blotting. Further, structural characterization demonstrates the instability of SigB in comparison to SigA that is carried out using homology modeling and structure function relationship. We have done protein-protein docking of RNA polymerase (RNAP) of Msmeg and SigB. This effort provides a platform for pulldown assay, structural, and other studies with the recombinant protein to deduce the SigB interacting proteins, which might pave the way to study its signaling networks along with its regulation.
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Geijtenbeek, Teunis B. H., Sandra J. van Vliet, Estella A. Koppel, et al. "Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function." Journal of Experimental Medicine 197, no. 1 (2002): 7–17. http://dx.doi.org/10.1084/jem.20021229.
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Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis–infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.
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Pitarque, Sylvain, Jean-Louis Herrmann, Jean-Luc Duteyrat, et al. "Deciphering the molecular bases of Mycobacterium tuberculosis binding to the lectin DC-SIGN reveals an underestimated complexity." Biochemical Journal 392, no. 3 (2005): 615–24. http://dx.doi.org/10.1042/bj20050709.
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Interactions between dendritic cells and Mycobacterium tuberculosis, the aetiological agent of tuberculosis in humans, are thought to be central to anti-mycobacterial immunity. We have previously shown that M. tuberculosis binds to human monocyte-derived dendritic cells mostly through the C-type lectin DC-SIGN (dendritic-cell-specific intercellular molecule-3-grabbing non-integrin)/CD209, and we have suggested that DC-SIGN may discriminate between mycobacterial species through recognition of the mannose-capping residues on the lipoglycan lipoarabinomannan of the bacterial envelope. Here, using a variety of fast- and slow-growing Mycobacterium species, we provide further evidence that mycobacteria recognition by DC-SIGN may be restricted to species of the M. tuberculosis complex. Fine analyses of the lipoarabinomannan molecules purified from these species show that the structure and amount of these molecules alone cannot account for such a preferential recognition. We propose that M. tuberculosis recognition by DC-SIGN relies on both a potential difference of accessibility of lipoarabinomannan in its envelope and, more probably, on the binding of additional ligands, possibly including lipomannan, mannose-capped arabinomannan, as well as the mannosylated 19 kDa and 45 kDa [Apa (alanine/proline-rich antigen)] glycoproteins. Altogether, our results reveal that the molecular basis of M. tuberculosis binding to DC-SIGN is more complicated than previously thought and provides further insight into the mechanisms of M. tuberculosis recognition by the immune system.
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Saviola, Beatrice, Samuel C. Woolwine, and William R. Bishai. "Isolation of Acid-Inducible Genes of Mycobacterium tuberculosis with the Use of Recombinase-Based In Vivo Expression Technology." Infection and Immunity 71, no. 3 (2003): 1379–88. http://dx.doi.org/10.1128/iai.71.3.1379-1388.2003.
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ABSTRACT A better understanding of mycobacterial gene regulation under certain stress conditions (e.g., low pH) may provide insight into mechanisms of adaptation during infection. To identify mycobacterial promoters induced at low pH, we adapted the recombinase-based in vivo expression technology (RIVET) promoter trap system for use with mycobacteria. Our results show that the TnpR recombinase of transposon γδ is active in Mycobacterium smegmatis and Mycobacterium tuberculosis. We developed a method to perform sequential double selection with mycobacteria by using RIVET, with a kanamycin preselection and a sucrose postselection. A library of M. tuberculosis DNA inserted upstream of tnpR was created, and using the double selection, we identified two promoters which are upregulated at low pH. The promoter regions drive the expression of a gene encoding a putative lipase, lipF (Rv3487c), as well as a PE-PGRS gene, Rv0834c, in a pH-dependent manner in both M. smegmatis and M. tuberculosis. The acid inducibility of lipF and Rv0834c was independent of the stress response sigma factor, SigF, as acid induction of the two genes in an M. tuberculosis sigF mutant strain was similar to that in the wild-type strain. No induction of lipF or Rv0834c was observed during infection of J774 murine macrophages, an observation which is in agreement with previous reports on the failure of phagosomes containing M. tuberculosis to acidify.
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Fernandes, Norvin D., Qi-long Wu, Dequan Kong, Xiaoling Puyang, Sumeet Garg, and Robert N. Husson. "A Mycobacterial Extracytoplasmic Sigma Factor Involved in Survival following Heat Shock and Oxidative Stress." Journal of Bacteriology 181, no. 14 (1999): 4266–74. http://dx.doi.org/10.1128/jb.181.14.4266-4274.1999.
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ABSTRACT Extracytoplasmic function (ECF) sigma factors are a heterogeneous group of alternative sigma factors that regulate gene expression in response to a variety of conditions, including stress. We previously characterized a mycobacterial ECF sigma factor, SigE, that contributes to survival following several distinct stresses. A gene encoding a closely related sigma factor, sigH, was cloned fromMycobacterium tuberculosis and Mycobacterium smegmatis. A single copy of this gene is present in these and other fast- and slow-growing mycobacteria, including M. fortuitum and M. avium. While the M. tuberculosis and M. smegmatis sigH genes encode highly similar proteins, there are multiple differences in adjacent genes. The single in vivo transcriptional start site identified inM. smegmatis and one of two identified in M. bovis BCG were found to have −35 promoter sequences that match the ECF-dependent −35 promoter consensus. Expression from these promoters was strongly induced by 50°C heat shock. In comparison to the wild type, an M. smegmatis sigH mutant was found to be more susceptible to cumene hydroperoxide stress but to be similar in logarithmic growth, stationary-phase survival, and survival following several other stresses. Survival of an M. smegmatis sigH sigE double mutant was found to be markedly decreased following 53°C heat shock and following exposure to cumene hydroperoxide. Expression of the second gene in the sigH operon is required for complementation of the sigH stress phenotypes. SigH is an alternative sigma factor that plays a role in the mycobacterial stress response.
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Williams, Diana L., Tana L. Pittman, Mike Deshotel, Sandra Oby-Robinson, Issar Smith, and Robert Husson. "Molecular Basis of the Defective Heat Stress Response in Mycobacterium leprae." Journal of Bacteriology 189, no. 24 (2007): 8818–27. http://dx.doi.org/10.1128/jb.00601-07.
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ABSTRACT Mycobacterium leprae, a major human pathogen, grows poorly at 37°C. The basis for its inability to survive at elevated temperatures was investigated. We determined that M. leprae lacks a protective heat shock response as a result of the lack of transcriptional induction of the alternative sigma factor genes sigE and sigB and the major heat shock operons, HSP70 and HSP60, even though heat shock promoters and regulatory circuits for these genes appear to be intact. M. leprae sigE was found to be capable of complementing the defective heat shock response of mycobacterial sigE knockout mutants only in the presence of a functional mycobacterial sigH, which orchestrates the mycobacterial heat shock response. Since the sigH of M. leprae is a pseudogene, these data support the conclusion that a key aspect of the defective heat shock response in M. leprae is the absence of a functional sigH. In addition, 68% of the genes induced during heat shock in M. tuberculosis were shown to be either absent from the M. leprae genome or were present as pseudogenes. Among these is the hsp/acr2 gene, whose product is essential for M. tuberculosis survival during heat shock. Taken together, these results suggest that the reduced ability of M. leprae to survive at elevated temperatures results from the lack of a functional transcriptional response to heat shock and the absence of a full repertoire of heat stress response genes, including sigH.
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Tailleux, Ludovic, Olivier Schwartz, Jean-Louis Herrmann, et al. "DC-SIGN Is the Major Mycobacterium tuberculosis Receptor on Human Dendritic Cells." Journal of Experimental Medicine 197, no. 1 (2002): 121–27. http://dx.doi.org/10.1084/jem.20021468.
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Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mϕs), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis–derived material was detected in CD14−HLA-DR+DC-SIGN+ cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN–mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.
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Song, Taeksun, Seung-Eun Song, Sahadevan Raman, Mauricio Anaya, and Robert N. Husson. "Critical Role of a Single Position in the −35 Element for Promoter Recognition by Mycobacterium tuberculosis SigE and SigH." Journal of Bacteriology 190, no. 6 (2008): 2227–30. http://dx.doi.org/10.1128/jb.01642-07.
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ABSTRACT Mycobacterial SigE and SigH both initiate transcription from the sigB promoter, suggesting that they recognize similar sequences. Through mutational and primer extension analyses, we determined that SigE and SigH recognize nearly identical promoters, with differences at the 3′ end of the −35 element distinguishing between SigE- and SigH-dependent promoters.
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Karls, Russell K., Jeannette Guarner, David N. McMurray, Kristin A. Birkness, and Frederick D. Quinn. "Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis." Microbiology 152, no. 6 (2006): 1591–600. http://dx.doi.org/10.1099/mic.0.28591-0.
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Secondary sigma factors in bacteria direct transcription of defence regulons in response to specific stresses. To identify which sigma factors in the human respiratory pathogen Mycobacterium tuberculosis are important for adaptive survival in vivo, defined null mutations were created in individual sigma factor genes. In this study, in vitro growth virulence and guinea pig pathology of M. tuberculosis mutants lacking functional sigma factors (SigC, SigF, or SigM) were compared to the parent strain, H37Rv. None of the mutant strains exhibited a growth deficiency in Middlebrook 7H9 broth, nor were any impaired for intracellular replication in the human monocytic macrophage cell-line THP-1. Following low-dose aerosol infection of guinea pigs, however, differences could be detected. While a SigM mutant resulted in lung and spleen granulomas of comparable composition to those found in H37Rv-infected animals, a SigF mutant was partially attenuated, exhibiting necrotic spleen granulomas and ill-defined lung granulomas. SigC mutants exhibited attenuation in the lung and spleen; notably, necrotic granulomas were absent. These data suggest that while SigF may be important for survival in the lung, SigC is likely a key regulator of pathogenesis and adaptive survival in the lung and spleen. Understanding how SigC mediates survival in the host should prove useful in the development of anti-tuberculosis therapies.
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Raman, Sahadevan, Taeksun Song, Xiaoling Puyang, Stoyan Bardarov, William R. Jacobs, and Robert N. Husson. "The Alternative Sigma Factor SigH Regulates Major Components of Oxidative and Heat Stress Responses in Mycobacterium tuberculosis." Journal of Bacteriology 183, no. 20 (2001): 6119–25. http://dx.doi.org/10.1128/jb.183.20.6119-6125.2001.
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ABSTRACT Mycobacterium tuberculosis is a specialized intracellular pathogen that must regulate gene expression to overcome stresses produced by host defenses during infection. SigH is an alternative sigma factor that we have previously shown plays a role in the response to stress of the saprophyte Mycobacterium smegmatis. In this work we investigated the role ofsigH in the M.tuberculosis response to heat and oxidative stress. We determined that a M. tuberculosis sigHmutant is more susceptible to oxidative stresses and that the inducible expression of the thioredoxin reductase/thioredoxin genestrxB2/trxC and a gene of unknown function, Rv2466c, is regulated by sigH via expression from promoters directly recognized by SigH. We also determined that thesigH mutant is more susceptible to heat stress and that inducible expression of the heat shock genes dnaK andclpB is positively regulated by sigH. The induction of these heat shock gene promoters but not of other SigH-dependent promoters was markedly greater in response to heat versus oxidative stress, consistent with their additional regulation by a heat-labile repressor. To further understand the role ofsigH in the M.tuberculosis stress response, we investigated the regulation of the stress-responsive sigma factor genessigE and sigB. We determined that inducible expression of sigE is regulated bysigH and that basal and inducible expression ofsigB is dependent on sigE andsigH. These data indicate that sigH plays a central role in a network that regulates heat and oxidative-stress responses that are likely to be important in M.tuberculosis pathogenesis.
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Driessen, Nicole N., Roy Ummels, Janneke J. Maaskant, et al. "Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN." Infection and Immunity 77, no. 10 (2009): 4538–47. http://dx.doi.org/10.1128/iai.01256-08.
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ABSTRACT The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM6, which contains terminal α(1→2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM2 and PIM4, respectively. To determine the role of PIM6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM6 (ΔpimE) was created, as well as a double knockout deficient in the production of both PIM6 and the mannose caps on LAM (ΔpimE ΔcapA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.
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Michele, Theresa M., Chiew Ko, and William R. Bishai. "Exposure to Antibiotics Induces Expression of theMycobacterium tuberculosis sigF Gene: Implications for Chemotherapy against Mycobacterial Persistors." Antimicrobial Agents and Chemotherapy 43, no. 2 (1999): 218–25. http://dx.doi.org/10.1128/aac.43.2.218.
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ABSTRACT The sigF gene encodes an alternate sigma factor found in Mycobacterium tuberculosis and related pathogenic mycobacteria. Determination of conditions of sigFexpression is an important step in understanding the conditional gene regulation which may govern such processes as virulence and dormancy in mycobacteria. We constructed an in-frame translationallacZ-kan fusion within the sigF gene to determine the conditions of sigF expression. This reporter construct was expressed from a multicopy plasmid in a strain of BCG harboring an integrated luciferase reporter gene under the control of the mycobacteriophage L5 gp71 promoter. Antibiotic exposure, in particular, ethambutol, rifampin, streptomycin, and cycloserine treatment, increased the level of SigF reporter specific expression in a dose-dependent fashion. The level of SigF reporter specific expression increased over 100-fold in late-stationary-phase growth compared to that in exponential growth. During the exponential phase, SigF specific expression could be induced by a number of other stresses. Anaerobic metabolism induced SigF by greater than 150-fold, particularly in the presence of metronidazole. Cold shock increased the level of SigF specific expression, while heat shock decreased it. Oxidative stress was also an important inducer of SigF specific expression; a greater induction was seen with cumene hydroperoxide than with hydrogen peroxide. Comparisons of bacterial viability as determined by the luciferase assay or by plating serial dilutions revealed that luciferase gp71-dependent activity was an unreliable predictor of the numbers of CFU during stationary-phase growth and anaerobic metabolism. The induction of sigF following antibiotic exposure suggests that this bacterial transcription factor may control genes which are important for mycobacterial persistence in the host during chemotherapy.
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Zhou, Ying, Tianying Zhong, Wenjing Wei, et al. "Single START-domain protein Mtsp17 is involved in transcriptional regulation in Mycobacterium smegmatis." PLOS ONE 16, no. 4 (2021): e0249379. http://dx.doi.org/10.1371/journal.pone.0249379.
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Tuberculosis caused by the pathogen Mycobacterium tuberculosis (MTB), remains a significant threat to global health. Elucidating the mechanisms of essential MTB genes provides an important theoretical basis for drug exploitation. Gene mtsp17 is essential and is conserved in the Mycobacterium genus. Although Mtsp17 has a structure closely resembling typical steroidogenic acute regulatory protein-related lipid transfer (START) family proteins, its biological function is different. This study characterizes the transcriptomes of Mycobacterium smegmatis to explore the consequences of mtsp17 downregulation on gene expression. Suppression of the mtsp17 gene resulted in significant down-regulation of 3% and upregulation of 1% of all protein-coding genes. Expression of desA1, an essential gene involved in mycolic acid synthesis, and the anti-SigF antagonist MSMEG_0586 were down-regulated in the conditional Mtsp17 knockout mutant and up-regulated in the Mtsp17 over-expression strain. Trends in the changes of 70 of the 79 differentially expressed genes (Log2 fold change > 1.5) in the conditional Mtsp17 knockout strain were the same as in the SigF knockout strain. Our data suggest that Mtsp17 is likely an activator of desA1 and Mtsp17 regulates the SigF regulon by SigF regulatory pathways through the anti-SigF antagonist MSMEG_0586. Our findings indicate the role of Mtsp17 may be in transcriptional regulation, provide new insights into the molecular mechanisms of START family proteins, and uncover a new node in the regulatory network of mycobacteria.
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Tanne, Antoine, Bo Ma, Frédéric Boudou, et al. "A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis." Journal of Experimental Medicine 206, no. 10 (2009): 2205–20. http://dx.doi.org/10.1084/jem.20090188.
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The C-type lectin dendritic cell−specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) mediates the innate immune recognition of microbial carbohydrates. We investigated the function of this molecule in the host response to pathogens in vivo, by generating mouse lines lacking the DC-SIGN homologues SIGNR1, SIGNR3, and SIGNR5. Resistance to Mycobacterium tuberculosis was impaired only in SIGNR3-deficient animals. SIGNR3 was expressed in lung phagocytes during infection, and interacted with M. tuberculosis bacilli and mycobacterial surface glycoconjugates to induce secretion of critical host defense inflammatory cytokines, including tumor necrosis factor (TNF). SIGNR3 signaling was dependent on an intracellular tyrosine-based motif and the tyrosine kinase Syk. Thus, the mouse DC-SIGN homologue SIGNR3 makes a unique contribution to protection of the host against a pulmonary bacterial pathogen.
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Hartkoorn, Ruben C., Claudia Sala, Sophie J. Magnet, Jeffrey M. Chen, Florence Pojer, and Stewart T. Cole. "Sigma Factor F Does Not Prevent Rifampin Inhibition of RNA Polymerase or Cause Rifampin Tolerance in Mycobacterium tuberculosis." Journal of Bacteriology 192, no. 20 (2010): 5472–79. http://dx.doi.org/10.1128/jb.00687-10.
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ABSTRACT The tolerance of Mycobacterium tuberculosis to antituberculosis drugs is a major reason for the lengthy therapy needed to treat a tuberculosis infection. Rifampin is a potent inhibitor of RNA polymerase (RNAP) in vivo but has been shown to be less effective against stationary-phase bacteria. Sigma factor F is associated with bacteria entering stationary phase and has been proposed to impact rifampin activity. Here we investigate whether RNAP containing SigF is more resistant to rifampin inhibition in vitro and whether overexpression of sigF renders M. tuberculosis more tolerant to rifampin. Real-time and radiometric in vitro transcription assays revealed that rifampin equally inhibits transcription by RNAP containing sigma factors SigA and SigF, therefore ruling out the hypothesis that SigF may be responsible for increased resistance of the enzyme to rifampin in vitro. In addition, overexpression or deletion of sigF did not alter rifampin susceptibility in axenic cultures of M. tuberculosis, indicating that SigF does not affect rifampin tolerance in vivo.
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Lee, Jong-Hee, Petros C. Karakousis, and William R. Bishai. "Roles of SigB and SigF in the Mycobacterium tuberculosis Sigma Factor Network." Journal of Bacteriology 190, no. 2 (2007): 699–707. http://dx.doi.org/10.1128/jb.01273-07.
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ABSTRACTTo characterize the roles of SigB and SigF in sigma factor regulation inMycobacterium tuberculosis, we used chemically inducible recombinant strains to conditionally overexpresssigBandsigF.Using whole genomic microarray analysis and quantitative reverse transcription-PCR, we investigated the resulting global transcriptional changes aftersigBinduction, and we specifically tested the relative expression of other sigma factor genes after knock-in expression ofsigBandsigF. Overexpression ofsigBresulted in significant upregulation of genes encoding several early culture filtrate antigens (ESAT-6-like proteins), ribosomal proteins, PE-PGRS proteins, the keto-acyl synthase, KasA, and the regulatory proteins WhiB2 and IdeR. Of note, the induction ofsigBdid not alter the expression of other sigma factor genes, indicating that SigB is likely to serve as an end regulator for at least one branch of theM. tuberculosissigma factor regulatory cascade. Analysis of the 5′-untranslated region (UTR) of SigB-dependent transcripts revealed a putative consensus sequence of NGTGG-N14-18-NNGNNG. This sequence appeared upstream of bothsigB(Rv2710) and the gene following it,ideR(Rv2711), and in vitro transcription analysis with recombinant SigB-reconstituted RNA polymerase confirmed SigB-dependent transcription from each of these promoters. Knock-in expression ofsigFrevealed that only thesigCgene was significantly upregulated 6 and 12 h aftersigFinduction. The previously identified SigF promoter consensus sequence AGTTTG-N15-GGGTTT was identified in the 5′ UTR of thesigCgene, and SigF-dependent in vitro transcription of the promoter upstream ofsigCwas confirmed by using recombinant SigF-reconstituted RNA polymerase. These two knock-in recombinant strains were tested in a macrophage model of infection which showed that overexpression ofsigBandsigFresulted in reduced rates ofM. tuberculosisintracellular growth. These results define the SigB promoter consensus recognition sequence and members of the SigB regulon. Moreover, the data suggest that, in addition to serving as an end regulator in a sigma factor cascade, SigB may auto-amplify its own expression under certain conditions.
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Talaat, Adel M., Sarah K. Ward, Chia-Wei Wu, et al. "Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling." Journal of Bacteriology 189, no. 11 (2007): 4265–74. http://dx.doi.org/10.1128/jb.00011-07.
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ABSTRACT Chronic tuberculosis represents a major health problem for one-third of the world's population today. A key question relevant to chronic tuberculosis is the physiological status of Mycobacterium tuberculosis during this important stage of infection. To examine the molecular bases of chronic tuberculosis and the role of host immunity in mycobacterial growth, we determined the mycobacterial transcriptional profiles during chronic and reactivation phases of murine tuberculosis using in vivo microarray analysis (IVMA). Following 28 days of aerosol infection, mycobacterial counts remained stable, although the bacilli were metabolically active with a 50% active transcriptome. The expression of genes involved in lipid and carbohydrate pathways was significantly enriched during the middle stage of chronic tuberculosis, suggesting a nutrient-rich microenvironment. A total of 137 genes were significantly regulated in mid-chronic tuberculosis (45 and 60 days) compared to an early stage (14 days) of infection. Additional sets of genes, including the virulence regulator virS, were up-regulated during the reactivation stage, indicating their possible roles in mycobacterial resurgence. Interestingly, a set of potential transcriptional regulators was significantly induced at the late stage of chronic tuberculosis. Bioinformatic analysis identified a large number of genes that could be regulated by one of the potential transcriptional regulators encoded by rv0348, including the sigF operon. Taken together, IVMA provided a better definition of the transcriptional machinery activated during chronic and reactivation stages of tuberculosis and identified a novel transcriptional regulator. A similar approach can be adopted to study key stages of intracellular pathogens.
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Pouget, Marion, Anna K. Coussens, Alessandra Ruggiero, et al. "Generation of Liposomes to Study the Effect of Mycobacterium Tuberculosis Lipids on HIV-1 cis- and trans-Infections." International Journal of Molecular Sciences 22, no. 4 (2021): 1945. http://dx.doi.org/10.3390/ijms22041945.
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Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis (Mtb) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection (cis- and trans-infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic (Mycobacterium bovis BCG and Mycobacterium smegmatis) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis- and trans-infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans-infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M. bovis, Mtb H37Rv and Mtb EU127 strains when using Raji-DC-SIGN cells or immature and mature dendritic cells (DCs) to capture virus. SL1, PDIM and TDM lipids were identified to be involved in DC-SIGN recognition and impairment of HIV-1 trans-infection. These findings indicate that variant strains of Mtb have differential effect on HIV-1 trans-infection with the potential to influence HIV-1 disease course in co-infected individuals.
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He, Hongjun, Raymond Hovey, Jason Kane, Vineet Singh, and Thomas C. Zahrt. "MprAB Is a Stress-Responsive Two-Component System That Directly Regulates Expression of Sigma Factors SigB and SigE in Mycobacterium tuberculosis." Journal of Bacteriology 188, no. 6 (2006): 2134–43. http://dx.doi.org/10.1128/jb.188.6.2134-2143.2006.
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ABSTRACT The genetic mechanisms mediating the adaptation of Mycobacterium tuberculosis within the host are poorly understood. The best-characterized regulatory systems in this organism include sigma factors and two-component signal transduction systems. mprAB is a two-component system required by M. tuberculosis for growth in vivo during the persistent stage of infection. In this report, we demonstrate that MprAB is stress responsive and regulates the expression of numerous stress-responsive genes in M. tuberculosis. With DNA microarrays and quantitative real-time reverse transcription-PCR, genes regulated by MprA in M. tuberculosis that included two stress-responsive sigma factors were identified. Response regulator MprA bound to conserved motifs in the upstream regions of both sigB and sigE in vitro and regulated the in vivo expression of sigB and sigE in M. tuberculosis. In addition, mprA itself was induced following exposure to stress, establishing a direct role for this regulatory system in stress response pathways of M. tuberculosis. Induction of mprA and sigE by MprA in response to stress was mediated through the cognate sensor kinase MprB and required expression of the extracytoplasmic loop domain. These results provide the first evidence that recognition of and adaptation to specific stress in M. tuberculosis are mediated through activation of a two-component signal transduction system that directly regulates the expression of stress-responsive determinants.
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Williams, Ernest P., Jong-Hee Lee, William R. Bishai, Carlo Colantuoni, and Petros C. Karakousis. "Mycobacterium tuberculosis SigF Regulates Genes Encoding Cell Wall-Associated Proteins and Directly Regulates the Transcriptional Regulatory Gene phoY1." Journal of Bacteriology 189, no. 11 (2007): 4234–42. http://dx.doi.org/10.1128/jb.00201-07.
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ABSTRACT Mycobacterium tuberculosis SigF is homologous to stress response and sporulation sigma factors in many bacteria. Consistent with a possible role in mycobacterial survival under stress conditions, M. tuberculosis sigF is strongly induced within cultured human macrophages and upon nutrient starvation, and SigF has been implicated in M. tuberculosis entry into stationary phase. On the other hand, SigF appears to contribute to the immune pathology of tuberculosis (TB), and a sigF-deficient mutant has altered cell membrane properties. Using an M. tuberculosis sigF deletion mutant, we show here that sigF is not required for bacillary survival under nutrient starvation conditions and within activated murine macrophages or for extracellular persistence in an in vivo granuloma model of latent TB infection. Using a chemically inducible recombinant strain to conditionally overexpress sigF, we did not observe arrest or retardation of growth in exponentially growing cultures or reduced susceptibility to rifampin and isoniazid. Consistent with our hypothesis that SigF may mediate TB immunopathogenesis by altering cell membrane properties, we found that overexpression of sigF resulted in the differential regulation of many cell wall-associated proteins, including members of the MmpL, PE, and PPE families, several of which have been shown to influence host-pathogen interactions. The most highly upregulated gene by quantitative reverse transcription-PCR at all time points following sigF induction was Rv3301c (phoY1), which encodes a probable transcriptional regulatory protein homologous to PhoU proteins involved in regulation of phosphate uptake. Using in vitro transcription analysis, we show that SigF directly regulates phoY1, whose proposed promoter sequence is GGATTG-N16-GGGTAT.
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Agarwal, Nisheeth, Samuel C. Woolwine, Sandeep Tyagi, and William R. Bishai. "Characterization of the Mycobacterium tuberculosis Sigma Factor SigM by Assessment of Virulence and Identification of SigM-Dependent Genes." Infection and Immunity 75, no. 1 (2006): 452–61. http://dx.doi.org/10.1128/iai.01395-06.
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ABSTRACT Alternate sigma factors have been implicated in the survival of mycobacteria in response to specific stresses. To characterize the role of SigM in Mycobacterium tuberculosis, a sigM deletion mutant was generated by allelic exchange in the virulent CDC1551 strain. Comparing the wild-type and ΔsigM strains by complete genomic microarray, we observed a low level of baseline expression of sigM in wild-type M. tuberculosis and no significant differences in the gene expression patterns between these two strains. Alternatively, a SigM-overexpressing M. tuberculosis strain was constructed and microarray profiling revealed SigM-dependent expression of a relatively small group of genes, which included four esat-6 homologues: esxE, esxF, esxT, and esxU. An assessment of SigM-dependent promoters from the microarray analysis revealed a putative consensus sequence for M. tuberculosis SigM of −35 GGAAC and −10 CGTCR. In vitro expression studies showed that M. tuberculosis sigM transcripts accumulate slightly in stationary phase and following heat shock. To understand the role of SigM in pathogenesis, the M. tuberculosis sigM deletion strain was compared with the isogenic wild-type strain and the complemented mutant strain for survival in murine macrophages and in the mouse model. The mutant was found to have similar abilities to survive in both the resting and activated J774A.1 macrophages. Mouse organ bacterial burdens indicated that the mutant proliferated and persisted at the same level as that of the wild-type and complemented strains in lung and spleen tissues. In time-to-death experiments in the mouse model, the ΔsigM mutant exhibited lethality times comparable to those observed for the wild-type and complemented strains. These data indicate that M. tuberculosis SigM governs the expression of a small set of genes, including four esat-6 homologues, and that the loss of sigM does not confer a detectable virulence defect in the macrophages and mouse models of infection.
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Roberts, Esteban A., Amanda Clark, Sarah McBeth, and Richard L. Friedman. "Molecular Characterization of the eis Promoter of Mycobacterium tuberculosis." Journal of Bacteriology 186, no. 16 (2004): 5410–17. http://dx.doi.org/10.1128/jb.186.16.5410-5417.2004.
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ABSTRACT To further understand Mycobacterium tuberculosis pathogenesis, the regulation of potential virulence genes needs to be investigated. The eis gene of M. tuberculosis H37Rv enhances the intracellular survival of Mycobacterium smegmatis, which does not contain eis, within macrophages (J. Wei, J. L. Dahl, J. W. Moulder, E. A. Roberts, P. O'Gaora, D. B. Young, and R. L. Friedman, J. Bacteriol. 182:377-384, 2000). Experiments were done to characterize the eis promoter in M. smegmatis and M. tuberculosis H37Ra. The putative −10 and −35 regions matched the Escherichia coli σ70 consensus 67 and 83%, respectively, making it a group A/SigA-like mycobacterial promoter. Expression of site-directed variants of the core promoter region, determined by flow cytometry using gfp as a reporter, showed that the putative −10 region is essential for eis expression. In addition, site-directed alteration of the eis promoter to the consensus E. coli σ70 promoter elements increased gfp transcription to levels similar to that driven by the heat shock promoter, phsp60, of Mycobacterium bovis BCG. Upstream promoter deletion analysis showed that a 200- and 412-bp region of the promoter was necessary for maximum expression of gfp in M. smegmatis and M. tuberculosis H37Ra, respectively. Random mutagenesis of the 412-bp eis promoter, using a catechol 2,3-dioxygenase screen and activity assay, defined nucleotides upstream of the core promoter region that are essential to eis expression in both M. smegmatis and M. tuberculosis H37Ra, including a region homologous to a DinR cis element.
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Sankar, Poornima, Mohd Saqib, Tanvir Noor Nafiz, and Bibhuti B. Mishra. "M. tuberculosisinduced alterations in Siglecs’ expression on neutrophils predicts susceptibility to infection." Journal of Immunology 210, no. 1_Supplement (2023): 156.03. http://dx.doi.org/10.4049/jimmunol.210.supp.156.03.
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Abstract The Presence of neutrophils in tuberculosis (TB) lung lesions is associated with bacterial growth. Despite being potent microbicidal cells, why neutrophils in TB lesions fail to control bacterial replication is poorly understood. By infecting mice with a hypervirulent replication reporter Mycobacterium tuberculosis(Mtb) W-Beijing Strain HN878, we found elevated neutrophils containing bacteria, associated with host susceptibility to infection. Phenotypic characterization of neutrophils from infected lungs revealed a downregulation of canonical neutrophil marker Siglec E (SigE) with concomitant upregulation of Siglec H (SigH), a marker generally used to define plasmacytoid dendritic cells. SigH expression on lung neutrophils increased with disease progression and predicts susceptibility to TB. Importantly, these non-conventional Ly6G+SigH+ neutrophils harbored more replicating bacteria compared to Ly6G+SigH-SigE+ lung neutrophils. In-vitroinfection of naïve bone marrow neutrophils showed enhanced SigH expression with increased infectivity, and this was dependent on glycolysis and fatty acid metabolism. Treatment of immunocompetent mice with neutralizing antibodies for SigH reduced live cell bacterial burden, neutrophil infiltration, restricted bacterial replication and increased neutrophil expression of SigE. Further, SigH neutralized mice also showed elevated T cell numbers, indicating protective immunity. Collectively, our data suggests a model where Mtb induces SigH expression on neutrophils to survive within them, as a potential immune evasion strategy. Our future studies will determine the functional significance of this alteration in Siglecs on neutrophils and its role in TB pathogenesis. R56 AI148239-01A1 and R21AI16359 (sub-award) from NIH/NIAID toDr. Bibhuti B Mishra
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Wu, Chia-wei, Shelly K. Schmoller, Sung Jae Shin, and Adel M. Talaat. "Defining the Stressome of Mycobacterium avium subsp. paratuberculosis In Vitro and in Naturally Infected Cows." Journal of Bacteriology 189, no. 21 (2007): 7877–86. http://dx.doi.org/10.1128/jb.00780-07.
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ABSTRACT Mycobacterium avium subsp. paratuberculosis causes an enteric infection in cattle, with a great impact on the dairy industry in the United States and worldwide. Characterizing the gene expression profile of M. avium subsp. paratuberculosis exposed to different stress conditions, or shed in cow feces, could improve our understanding of the pathogenesis of M. avium subsp. paratuberculosis. In this report, the stress response of M. avium subsp. paratuberculosis on a genome-wide level (stressome) was defined for the first time using DNA microarrays. Expression data analysis revealed unique gene groups of M. avium subsp. paratuberculosis that were regulated under in vitro stressors while additional groups were regulated in the cow samples. Interestingly, acidic pH induced the regulation of a large number of genes (n = 597), suggesting the high sensitivity of M. avium subsp. paratuberculosis to acidic environments. Generally, responses to heat shock, acidity, and oxidative stress were similar in M. avium subsp. paratuberculosis and Mycobacterium tuberculosis, suggesting common pathways for mycobacterial defense against stressors. Several sigma factors (e.g., sigH and sigE) were differentially coregulated with a large number of genes depending on the type of each stressor. Subsequently, we analyzed the virulence of six M. avium subsp. paratuberculosis mutants with inactivation of differentially regulated genes using a murine model of paratuberculosis. Both bacterial and histopathological examinations indicated the attenuation of all gene mutants, especially those selected based on their expression in the cow samples (e.g., lipN). Overall, the employed approach profiled mycobacterial genetic networks triggered by variable stressors and identified a novel set of putative virulence genes. A similar approach could be applied to analyze other intracellular pathogens.
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White, Mark J., Hongjun He, Renee M. Penoske, Sally S. Twining, and Thomas C. Zahrt. "PepD Participates in the Mycobacterial Stress Response Mediated through MprAB and SigE." Journal of Bacteriology 192, no. 6 (2010): 1498–510. http://dx.doi.org/10.1128/jb.01167-09.
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ABSTRACT Currently, one-third of the world's population is believed to be latently infected with Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis establishes latent infection remain largely undefined. mprAB encodes a two-component signal transduction system required by M. tuberculosis for aspects of persistent infection. MprAB regulates a large and diverse group of genetic determinants in response to membrane stress, including the extracytoplasmic function (ECF) sigma factor sigE and the HtrA-like serine protease pepD. Recent studies have demonstrated that PepD functions as both a protease and chaperone in vitro. In addition, inactivation of pepD alters the virulence of M. tuberculosis in a mouse model system of infection. Here, we demonstrate that PepD plays an important role in the stress response network of Mycobacterium mediated through MprAB and SigE. In particular, we demonstrate that the protease activity of PepD requires the PDZ domain, in addition to the catalytic serine at position 317. pepD expression initiates from at least three promoters in M. tuberculosis, including one that is regulated by SigE and is located upstream of the mprA coding sequence. Deletion of pepD or mprAB in Mycobacterium smegmatis and M. tuberculosis alters the stress response phenotypes of these strains, including increasing sensitivity to SDS and cell wall antibiotics and upregulating the expression of stress-responsive determinants, including sigE. Taking these data together, we hypothesize that PepD utilizes its PDZ domain to recognize and process misfolded proteins at the cell membrane, leading to activation of the MprAB and SigE signaling pathways and subsequent establishment of a positive feedback loop that facilitates bacterial adaptation.
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Pang, Xiuhua, та Susan T. Howard. "Regulation of the α-Crystallin Gene acr2 by the MprAB Two-Component System of Mycobacterium tuberculosis". Journal of Bacteriology 189, № 17 (2007): 6213–21. http://dx.doi.org/10.1128/jb.00492-07.
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ABSTRACT Coordinated regulation of molecular chaperones is an important feature of the bacterial stress response. The small molecular chaperone gene acr2 of Mycobacterium tuberculosis is activated by exposure to several stresses, including heat and the detergent sodium dodecyl sulfate (SDS). In this study, we show that acr2 is directly regulated by the MprAB two-component system, and that MprAB has both positive and negative effects on acr2 expression. mRNA analyses showed that acr2 expression levels were lower under SDS stress and control conditions but higher under heat shock in an mprAB deletion mutant than they were in the parental strain. Parental expression patterns were restored in an mprAB-complemented strain. Western blotting using an anti-Acr2 antibody showed that Acr2 protein synthesis correlated with mRNA levels. Primer extension identified one transcriptional start point (TSP) for acr2 in all three strains under control and stress conditions. Electrophoresis mobility shift assays revealed multiple MprA binding sites in the acr2 promoter, including one downstream and three upstream of the acr2 TSP, with one overlapping the binding sites predicted for SigE, SigH, and HspR. DNA footprinting confirmed that MprA protected large sections of the acr2 promoter region. Expression of several housekeeping genes under SDS stress also was evaluated, revealing the upregulation of large molecular chaperone genes and, unexpectedly, sigA, with slightly lower sigA mRNA levels detected in the mprAB deletion mutant than in the wild type. In contrast to Acr2, SigA protein synthesis did not correlate with mRNA expression. Overall, the data indicated that MprA has complex interactions with the acr2 promoter and indirect effects on major housekeeping genes.
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Yimcharoen, Manita, Sukanya Saikaew, Usanee Wattananandkul, et al. "Mycobacterium tuberculosis Adaptation in Response to Isoniazid Treatment in a Multi-Stress System That Mimics the Host Environment." Antibiotics 12, no. 5 (2023): 852. http://dx.doi.org/10.3390/antibiotics12050852.
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Isoniazid (INH) is an antibiotic that is widely used to treat tuberculosis (TB). Adaptation to environmental stress is a survival strategy for Mycobacterium tuberculosis and is associated with antibiotic resistance development. Here, mycobacterial adaptation following INH treatment was studied using a multi-stress system (MS), which mimics host-derived stress. Mtb H37Rv (drug-susceptible), mono-isoniazid resistant (INH-R), mono-rifampicin resistant (RIF-R), and multidrug-resistant (MDR) strains were cultivated in the MS with or without INH. The expression of stress-response genes (hspX, tgs1, icl1, and sigE) and lipoarabinomannan (LAM)-related genes (pimB, mptA, mptC, dprE1, dprE2, and embC), which play important roles in the host–pathogen interaction, were measured using real-time PCR. The different adaptations of the drug-resistant (DR) and drug-susceptible (DS) strains were presented in this work. icl1 and dprE1 were up-regulated in the DR strains in the MS, implying their roles as markers of virulence and potential drug targets. In the presence of INH, hspX, tgs1, and sigE were up-regulated in the INH-R and RIF-R strains, while icl1 and LAM-related genes were up-regulated in the H37Rv strain. This study demonstrates the complexity of mycobacterial adaptation through stress response regulation and LAM expression in response to INH under the MS, which could potentially be applied for TB treatment and monitoring in the future.
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Lee, Jong-Hee, Deborah E. Geiman, and William R. Bishai. "Role of Stress Response Sigma Factor SigG in Mycobacterium tuberculosis." Journal of Bacteriology 190, no. 3 (2007): 1128–33. http://dx.doi.org/10.1128/jb.00511-07.
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ABSTRACT The sigG gene of Mycobacterium tuberculosis was disrupted by homologous recombination, and the genes regulated by SigG were examined by real-time reverse-transcription PCR and microarray studies. The SigG consensus promoter recognition sequence was identified as GCGNGT-N15-18-CGANCA. A ΔsigG mutant was found to be more resistant to mitomycin C treatment than the wild-type strain, indicating that it may be involved in the SOS response in M. tuberculosis.
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Durkin, H. G., S. M. Chice, E. Gaetjens, H. Bazin, L. Tarcsay, and P. Dukor. "Origin and fate of IgE-bearing lymphocytes. II. Modulation of IgE isotype expression on Peyer's patch cells by feeding with certain bacteria and bacterial cell wall components or by thymectomy." Journal of Immunology 143, no. 6 (1989): 1777–83. http://dx.doi.org/10.4049/jimmunol.143.6.1777.
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Abstract Mechanisms regulating the appearance of sIgE+ B lymphocytes appear to be lacking in adult germfree (GF) rats in that their Peyer's patches (PP) contain high numbers of cells with sIgE (approximately 15% of total cells), one-half of which simultaneously express sIgA, whereas sIgE+ cells are absent from PP of conventional rats (less than 1%). GF rat PP also contain elevated numbers of sIgA+ cells and decreased numbers of sIgM+ cells, with elevated numbers of sThy-1+ RT 7.1+ Ig- T cells, and reduced numbers of sThy-1- RT 7.1+ Ig- T cells. The cellular composition of PP of GF rats was converted to that resembling a conventional rat within 18 h after either 1) use of standard (unautoclaved) food; 2) feeding with certain bacteria (Clostridium difficile, Corynebacterium pseudodiphtheriticum, Mycobacterium tuberculosis, and Klebsiella pneumoniae), in either live or heat-killed, but not autoclaved form; or with certain bacterial cell wall components: murein (peptidoglycan), and its synthetic derivatives, muramyltripeptide phosphatidylethanolamine and desmethyl-muramyldipeptide, but not with LPS, core lipid A or lipoprotein; there was no effect if any bacterial cell wall component was injected i.v.; or 3) thymectomy. Each procedure resulted in elimination of sIgE+ B cells and normalization of the other surface isotypes, and loss of sThy-1+ RT 7.1+ Ig- T cells and normalization of sThy-1- RT 7.1+ Ig- T cells. Irrespective of treatment, no sIgE+ cells were detected in bone marrow, thymus, other lymphoid organs or blood, excluding the possibility that the elimination of these cells from PP was associated with their redistribution to other sites. Thus, exposure to gut flora and bacterial peptidoglycan components may have resulted in IgE isotype switching, either directly or through the mediation of accessory and/or sThy-1+ RT 7.1+ regulatory T cells. The sites in which sIgE+ B cells are down-regulated appear to be PP.
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Mendelson, Marc, Willem A. Hanekom, Siyabulela Ntutela, et al. "Quantitative and Functional Differences between Peripheral Blood Myeloid Dendritic Cells from Patients with Pleural and Parenchymal Lung Tuberculosis." Clinical and Vaccine Immunology 13, no. 12 (2006): 1299–306. http://dx.doi.org/10.1128/cvi.00132-06.
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ABSTRACT Dendritic cells (DCs) play a pivotal role in generating protective host immunity to Mycobacterium tuberculosis. Few studies have addressed DC function in the context of active tuberculosis (TB), largely due to technical constraints in obtaining adequate numbers of DC from sick patients. We quantitated peripheral blood myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the whole blood of patients with active TB and show that blood from patients with pleural TB was characterized by high circulating levels of mDCs. We also developed and optimized a novel whole-blood assay to study mDC production of the Th1-promoting cytokine interleukin 12 (IL-12) and upregulation of the maturation marker CCR7 after incubation with mycobacteria. We found that pleural TB was associated with increased IL-12 production and CCR7 expression compared to lung parenchymal disease. Our findings suggest important differences in innate immunity between patients with different forms of active TB, and this may contribute to the differences in natural history observed between the two groups.
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Fontán, P. A., M. I. Voskuil, M. Gomez та ін. "The Mycobacterium tuberculosis Sigma Factor σB Is Required for Full Response to Cell Envelope Stress and Hypoxia In Vitro, but It Is Dispensable for In Vivo Growth". Journal of Bacteriology 191, № 18 (2009): 5628–33. http://dx.doi.org/10.1128/jb.00510-09.
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ABSTRACT The numerous sigma (σ) factors present in Mycobacterium tuberculosis are indicative of the adaptability of this pathogen to different environmental conditions. In this report, we describe the M. tuberculosis σB regulon and the phenotypes of an M. tuberculosis sigB mutant strain exposed to cell envelope stress, oxidative stress, and hypoxia. The sigB mutant was especially defective in survival under hypoxic conditions in vitro, but it was not attenuated for growth in THP-1 cells or during mouse and guinea pig infection.
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Kukuh Judy Handojo, Rosida,. "POTENSI EKSTRAK KENCUR (Kaemferia galanga L.) SEBAGAI IMUNOMODULATOR PADA TIKUS MODEL YANG TERINFEKSI Mycobacterium tuberculosis." JURNAL ILMIAH FARMASI AKADEMI FARMASI JEMBER 3, no. 1 (2021): 8–13. http://dx.doi.org/10.53864/jifakfar.v3i1.37.
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Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Tuberculosis can infect anyone in the patient's environment. Someone with good body immunity conditions will avoid tuberculosis. Increased immunity for tuberculosis sufferers is very important. The active substances contained in plants such as flavonoids and essential oils are important components in supporting the body's immunity. One plant that contains flavonoids and essential oils is kencur (Kaemferia galanga L.). This study aims to prove the potential of kencur extract as an immunomodulator in model rat infected with Mycobacterium tuberculosis. This study was a laboratory experiment using the kencur extract (EK) and samples of rats as a model. The sample used was 30 animals which were divided into 6 groups. Group 1 was a healthy animal (Normal). Groups 2, 3, 4 and 5 were treatment groups consisting of sick animals given placebo treatment (control), rifampicin (R), EK (Kencur Extract) and CRK (Mixture of Rifampicin and Kencur). Group 6 was a normal group given EK then infected with Mycobacterium tuberculosis (NK). Modeling was done by infecting experimental animals using Mycobacterium tuberculosis. The infection was 30 days and the treatment was 21 days. The parameters in this study were leukocytes and Laju Endap Darah (LED). The results of the kencur extract phytochemical screening study showed the presence of flavonoids. The results of the treatment showed that differences in the number of Leukocytes and LEDs between the control group and the treatment (sig 0.05). These results indicate that kencur extract has the potential as an immunomodulator.Keywords : Kaemferia galanga, Mycobacterium tuberculosis, imunomodulator
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Fermada, Randa, Fauzar Fauzar, Roza Kurniati, and Irza Wahid. "Miliary Tuberculosis in Immunocompromised Patient Induced by Imatinib and Steroid." Jurnal Kesehatan Andalas 10, no. 3 (2022): 202. http://dx.doi.org/10.25077/jka.v10i3.1821.
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Miliary tuberculosis occurs due to the hematogenous spread of Mycobacterium Tuberculosis from the primary complex. The use of steroid and cytotoxic drugs increases the incidence of miliary tuberculosis. Typical manifestations of miliary tuberculosis is snowstorm appearance seen on chest x-ray and evidence of tuberculosis microorganism from the microbiological examination. It has been reported a 33 years old male patient was admitted to the hospital due to breathlessness, chronic coughing, fever, anorexia, weight loss and night sweating with a "damp shadow sign". Due to chronic myelogenous leukemia and autoimmune hemolytic anemia, the patient is known under imatinib and steroid therapy. There was no specific sign found from the physical examination. Chest x-ray showed snowstorm appearance. The patient underwent GeneXpert MTB/RIF, with the result low MTB detected. The patient was treated with a 2(HRZE)/4(HR) tuberculosis drugs regimen. Imatinib and steroid therapy was discontinued. 2-4 weeks of steroid usage with a daily dose equivalent to prednisone 15 mg increases the risk of activating a latent tuberculosis infection. Imatinib affects the response of T cells to Mycobacterium, thereby triggering tuberculosis reactivation. In this case, the diagnosis has been made from typical manifestations of tuberculosis, snowstorm appearance from the chest x-ray, and low MTB detected from GeneXpert MTB/RIF. It has been recommended to detect latent tuberculosis infection before using steroid and cytotoxic drugs.Keywords: imatinib, miliary tuberculosis, steroid
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Mohd, Yunus R., A. A. Ahmad, and A. R. Ahmad. "THUMB TUBERCULOSIS: A CASE REPORT." Orthopaedic Journal of Sports Medicine 8, no. 5_suppl5 (2020): 2325967120S0006. http://dx.doi.org/10.1177/2325967120s00068.
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Tuberculosis is caused by Mycobacterium tuberculosis, occurs in about 2 billion people. Approximately 8 million people/year develop the active form.1,2 Tuberculosis in the hand is manifested as osteomyelitis in carpals, metacarpals and phalanges.1 Musculoskeletal tuberculosis occurs, in most cases, through haematogenous dissemination from the primary focus. In immunosuppression circumstances, it is reactivated. Methods: 47 years old lady, who had underlying pulmonary tuberculosis on anti-TB medications since June 2018, presented to us for swelling over right thumb. Associated with tender, erythematous skin and limited range of motion of right thumb. Results: Plain radiograph demonstrated soft tissue swelling, joint space narrowing, mottled lucency of the proximal phalanx and cystic degenerative changes. MRI shows osteomylities proximal phalanx of right thumb. Patient underwent wound debridement of right thumb, culture and sensitivity shows Mycobacterium tuberculosis infections. Post debridement, range of motion of MCP joint of right thumb was improved and anti-TB medications to restart. Discussions: Tuberculosis involvement of the metacarpals and phalanges is a rare presentation of extrapulmonary TB. The radiographic features of osseous tuberculosis are present in conditions such as inflammatory arthritis, pyogenic osteomyelitis, osteopenia, softtissue swelling with minimal periosteal reaction, narrowing of the joint space, cysts in bone adjacent to joints, and subchondral erosions. The gold standard to diagnose is culture of Mycobacterium tuberculosis from bone tissue. Current treatment is a 2 month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 6 to 12 month regimen of isoniazid and rifampin. Conclusion: Finger swelling is a rare presenting sign of disseminated tuberculosis. Early biopsy and appropriate microbiologic testing can avoid diagnostic delay. References: Malaviya AN, et al. Best Pract Res Clin Rheumatol. 2003;17:319–43. Fortún J, et al. Mycobacterium tuberculosis infection? Medicine. 2010;10:3808–19. DOI: 10.1016/S0304-5412(10)70119-0.
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Korniienko, L. Y., A. V. Pyskun, V. V. Ukhovskyi, et al. "Retrospective analysis of the control and prevention of tuberculosis among cattle in Ukraine in the period 1994–2020." Regulatory Mechanisms in Biosystems 12, no. 2 (2021): 301–6. http://dx.doi.org/10.15421/022140.
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Bovine tuberculosis (bTB) – is a chronic infectious disease, the causative agent of which affects many species of mammals. It is a zoonosis caused by various types of mycobacteria in the complex Mycobacterium tuberculosis family Mycobacteriaceae. The most important etiological agent of bTB in cattle is M. bovis, which has been isolated from tuberculosis infected cattle for centuries. Livestock and species of the Bovidae family are the most susceptible to this pathogen and are the main reservoir species for animals and humans. In Ukraine, the main methods of diagnosing tuberculosis in animal husbandry are lifetime (clinical examination, allergic intradermal test with tuberculin), and postmortem techniques (pathological changes, bacteriological investigation). The authors performed a retrospective analysis of the epizootic situation of tuberculosis among cattle in Ukraine for the period 1994–2020 and conducted a critical assessment of the work done to prevent and control this disease. In total, over the last 27 years, 219 088 head of cattle with tuberculosis and 933 affected locations have been identified in Ukraine. The results of this work showed that in our country the epizootic situation of bovine tuberculosis on farms of various forms of ownership is fully controlled. The most active fight against tuberculosis was carried out during 1995–2015. In 1994–1997, the largest number of affected locations was registered, from 90 to 144, respectively, and the largest number of animals with tuberculosis – 21 395–33 474. In 1994–1995, the largest number of sick animals per one affected point was registered (371.9 and 471.7 head, respectively). Currently, official statistics show that many farms, especially in Vinnytska, Cherkaska and Kyivska regions, continue to show positive allergic reactions to tuberculin (46 898 reactions for the last 12 years). Applying diagnostic methods of research in complex (bacteriological, bioassay, molecular), excludes affection of cattle by pathogenic mycobacteria. This study showed that for the last 5 years no farms with confirmed pathological diagnosis by bacteriological methods have been registered and no culture of the pathogen from animals has been detected. Besides the scurpulous work of the veterinary service, in our opinion, the catastrophic decline in the number of cattle in Ukraine also had a significant impact on improving the epizootic situation regarding tuberculosis.
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Zhai, Weijie, Fengjuan Wu, Yiyuan Zhang, Yurong Fu, and Zhijun Liu. "The Immune Escape Mechanisms of Mycobacterium Tuberculosis." International Journal of Molecular Sciences 20, no. 2 (2019): 340. http://dx.doi.org/10.3390/ijms20020340.
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Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world became sick with tuberculosis. Mycobacterium tuberculosis (MTB) is an intracellular parasite that mainly attacks macrophages and inhibits their apoptosis. It can become a long-term infection in humans, causing a series of pathological changes and clinical manifestations. In this review, we summarize innate immunity including the inhibition of antioxidants, the maturation and acidification of phagolysosomes and especially the apoptosis and autophagy of macrophages. Besides, we also elaborate on the adaptive immune response and the formation of granulomas. A thorough understanding of these escape mechanisms is of major importance for the prevention, diagnosis and treatment of tuberculosis.
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Ando, Masaru, Tetsuyuki Yoshimatsu, Chiew Ko, Paul J. Converse, and William R. Bishai. "Deletionof Mycobacterium tuberculosis Sigma Factor E Results inDelayed Time to Death with Bacterial Persistence in the Lungsof Aerosol-InfectedMice." Infection and Immunity 71, no. 12 (2003): 7170–72. http://dx.doi.org/10.1128/iai.71.12.7170-7172.2003.
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ABSTRACT The stress-induced extracytoplasmic sigma factor E (SigE) of Mycobacterium tuberculosis shows increased expression after heat shock, sodium dodecyl sulfate treatment, and oxidative stress, as well as after phagocytosis in macrophages. We report that deletion of sigE results in delayed lethality in mice without a significant reduction of bacterial numbers in lungs.
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Demaio, J., Y. Zhang, C. Ko, and W. R. Bishai. "Mycobacterium tuberculosis sigF is part of a gene cluster with similarities to the Bacillus subtilis sigF and sigB operons." Tubercle and Lung Disease 78, no. 1 (1997): 3–12. http://dx.doi.org/10.1016/s0962-8479(97)90010-1.
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Pando, Rogelio Hernandez, Leon Diana Aguilar, Issar Smith, and Riccardo Manganelli. "Immunogenicity and Protection Induced by a Mycobacterium tuberculosissigE Mutant in a BALB/c Mouse Model of Progressive Pulmonary Tuberculosis." Infection and Immunity 78, no. 7 (2010): 3168–76. http://dx.doi.org/10.1128/iai.00023-10.
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ABSTRACT Tuberculosis is still one of the main challenges to human global health, leading to about two million deaths every year. One of the reasons for its success is the lack of efficacy of the widely used vaccine Mycobacterium bovis BCG. In this article, we analyze the potential use of an attenuated mutant of Mycobacterium tuberculosis H37Rv lacking the sigma factor σE as a live vaccine. We have demonstrated that BALB/c mice infected by the intratracheal route with this mutant strain showed significantly higher survival rates and less tissue damage than animals infected with the parental or complemented mutant strain. Although animals infected with the sigE mutant had low bacillary loads, their lungs showed significantly higher production of the protective factors gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and β-defensins than those of animals infected with the parental or complemented mutant strain. Moreover, we demonstrate that the sigE mutant, when inoculated subcutaneously, was more attenuated than BCG in immunodeficient nude mice, thus representing a good candidate for a novel attenuated live vaccine strain. Finally, when we used the sigE mutant as a subcutaneous vaccine, it was able to induce a higher level of protection than did BCG with both H37Rv and a highly virulent strain of M. tuberculosis (Beijing code 9501000). Taken together, our findings suggest that the sigE mutant is a very promising strain for the development of a new vaccine against tuberculosis.
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Tetrapoik, Jean Clamentyn, Kristiawan Prasetyo Agung Nugroho, and Fiane De Fretes. "Upaya Keluarga dalam Perawatan Klien TB Paru dengan Komorbid Diabetes Melitus Di Kota Salatiga." Jurnal Sains dan Kesehatan 2, no. 4 (2020): 331–39. http://dx.doi.org/10.25026/jsk.v2i4.159.
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Abstrak
 
 Tuberkulosis Paru dalah penyakit infeksius yang ditakuti oleh masyarakat karena sumber penularan yang cepat dari bakteri tahan asam (BTA). BTA adalah suatu basil aerobic tahan asam yang merupakan bakteri yang terdiri dari lapisan lilin dan asam lemak mikolat, lipid yang ada bisa mencapai 60% dari berat dinding sel. Kelompok BTA terdiri dari: Mycobacterium Tuberculosis, Mycobacterium africanum, Mycobacterium bovis dan Mycobacterium Leprae. Keluarga sangat penting untuk dilibatkan secara aktif untuk melakukan pencegahan penularan dalam rumah.Tugas dari keluarga adalah melakukan perawatan bagi anggota keluarga yang sakit dengan mencegah penularan. Penyakit Tb Paru akan semakin lama pengobatannya bila disertai dengan komorbid DM. Keluarga harus membuat pencegahan/ pengobatan lain untuk dapat membuat penderita sembuh dari kedua penyakit tersebut, sehingga tidak memperburuk kondisi penderita. Penelitian ini bertujuan untuk menggambarkan bentuk upaya penanganan dan pencegahan pada klien tuberkulosis paru dengan komorbid DM yang sedang menjalani proses pengobatan di Kota Salatiga. Penelitian menggunakan metode kualitatif dengan mendeskripsikan bagaimana upaya penanganan dan pencegahan dan penanganan Tb Paru yang disertai dengan komorbid DM dapat dilakukan oleh anggota keluarga klien.
 
 Abstract
 
 Pulmonary tuberculosis is infectious disease of being shunned by the community for its rapid transmission of bacteria is acid resistant ( smear ).Smear is a basil aerobic hold acid which is a bacterium that consists of layers of candles and fatty acids mikolat, lipids that there can be reached 60 % from heavy. cell wallThe group smear consisting of: , mycobacterium tuberculosis mycobacterium africanum, mycobacterium bovis and mycobacterium leprae.Family is very important to actively involved in preventing the contagion in rumah.tugas of the family is being treated for a sick family members by preventing the transmission of.A disease pulmonary tuberculosis will be the longer the treatment if accompanied by komorbid dm. Family had to make prevention / other treatments to make patients recovered from both of these diseases, so as not worsen the condition. sufferersThis study attempts to describe the form of efforts to handle and prevention on the client pulmonary tuberculosis with komorbid dm who is undergoing the process of treatment in the city salatiga.The research uses a qualitative methodology with described how efforts to handle and prevention and handling of pulmonary tuberculosis are accompanied by komorbid dm can be done by family members. clients.
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Manganelli, Riccardo, Lanfranco Fattorini, Dejiang Tan та ін. "The Extra Cytoplasmic Function Sigma Factor σE Is Essential for Mycobacterium tuberculosis Virulence in Mice". Infection and Immunity 72, № 5 (2004): 3038–41. http://dx.doi.org/10.1128/iai.72.5.3038-3041.2004.
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ABSTRACT The virulence of a Mycobacterium tuberculosis H37Rv sigE mutant was studied in immunodeficient and immunocompetent mice. The mutant was strongly attenuated in both animal models and induced formation of granulomas with different characteristics than those induced by the wild-type strain.
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Raman, Sahadevan, Rohan Hazra, Christopher C. Dascher, and Robert N. Husson. "Transcription Regulation by the Mycobacterium tuberculosis Alternative Sigma Factor SigD and Its Role in Virulence." Journal of Bacteriology 186, no. 19 (2004): 6605–16. http://dx.doi.org/10.1128/jb.186.19.6605-6616.2004.
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ABSTRACT Mycobacterium tuberculosis, an obligate mammalian pathogen, adapts to its host during the course of infection via the regulation of gene expression. Of the regulators of transcription that play a role in this response, several alternative sigma factors of M. tuberculosis have been shown to control gene expression in response to stresses, and some of these are required for virulence or persistence in vivo. For this study, we examined the role of the alternative sigma factor SigD in M. tuberculosis gene expression and virulence. Using microarray analysis, we identified several genes whose expression was altered in a strain with a sigD deletion. A small number of these genes, including sigD itself, the gene encoding the autocrine growth factor RpfC, and a gene of unknown function, Rv1815, appear to be directly regulated by this sigma factor. By identifying the in vivo promoters of these genes, we have determined a consensus promoter sequence that is putatively recognized by SigD. The expression of several genes encoding PE-PGRS proteins, part of a large family of related genes of unknown function, was significantly increased in the sigD mutant. We found that the expression of sigD is stable throughout log phase and stationary phase but that it declines rapidly with oxygen depletion. In a mouse infection model, the sigD mutant strain was attenuated, with differences in survival and the inflammatory response in the lung between mice infected with the mutant and those infected with the wild type.
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Duzhiy, I. D., G. P. Oleshchenko, I. Ya Gresko, and V. Ya Pak. "The level of neutrophil elastase as an indication for surgical treatment of pulmonary tuberculosis." Tuberculosis, Lung Diseases, HIV Infection, no. 1 (April 4, 2022): 53–57. http://dx.doi.org/10.30978/tb-2022-1-53.
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The pathogenesis of tuberculosis is complex. The participation of the proteolytic system in it is not in doubt, at least in the decay phase. Clarification of this link in the pathogenesis, in our opinion, will be able to expand the diagnostic capabilities and treatment of pulmonary tuberculosis, including surgery. However, in practice, the state of the proteolytic system and its components in tuberculosis have not been studied, which emphasizes the urgency of the problem.
 Objective — to study the level of neutrophil elastase (NE) as a leading enzyme of the proteolytic system in patients with pulmonary tuberculosis to expand the diagnostic possibilities in suspected tuberculosis and clarify its features and possible volume and indications for surgery.
 Materials and methods. Under our clinical observation were, 66 patients with pulmonary tuberculosis were divided into two groups depending on the resistance of Mycobacterium tuberculosis to anti-tuberculosis drugs. The first group consisted of 39 (59.1 %) individuals whose mycobacteria were susceptible to anti-TB medicines. The second group included 27 (40.9 %) patients with multidrug-resistant pulmonary tuberculosis.Results and discussion. In patients with susceptible forms of a specific process, the level of elastase was in the range of 35.2—215.1 nmol/min ⋅ ml and averaged 110.1 nmol/min ⋅ ml. In patients with multidrug-resistant tuberculosis (group II), the elastase level was in the range of 34.6—163.1 nmol/min ⋅ ml, which averaged 78.4 nmol/min ⋅ ml (p < 0.05). The highest level of NE (93.0 nmol/min ⋅ ml) occurred in patients with infiltrative pulmonary tuberculosis. In disseminated pulmonary tuberculosis, the level of NE was 74.5 nmol/min ⋅ ml, which is significantly less (18.5 nmol/min ⋅ ml, or 1.25 times) than in infiltrative tuberculosis. In tuberculoma, the level of elastase was 68.1 nmol/min ⋅ ml. In fibrocavernous pulmonary tuberculosis, the level was not the lowest (30.9 nmol/min ⋅ ml).
 Conclusions. The level of neutrophil elastase in patients with susceptible pulmonary tuberculosis compared to patients with multidrug-resistant pulmonary tuberculosis was significantly higher (1.4 times). Decreased levels of neutrophil elastase characterize the reduced activity of the proteolytic blood system and may be a sign of chronicization of tuberculosis, which justifies the use of surgical treatment.
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Grosse-Siestrup, Benjamin T., Tuhina Gupta, Shelly Helms, et al. "A Role for Mycobacterium tuberculosis Sigma Factor C in Copper Nutritional Immunity." International Journal of Molecular Sciences 22, no. 4 (2021): 2118. http://dx.doi.org/10.3390/ijms22042118.
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Sigma factor C (SigC) contributes to Mycobacterium tuberculosis virulence in various animal models, but the stress response coordinated by this transcription factor was undefined. The results presented here indicate that SigC prevents copper starvation. Whole genome expression studies demonstrate short-term (4-h) induction of sigC, controlled from a tetracycline-inducible promoter, upregulates ctpB and genes in the nonribosomal peptide synthase (nrp) operon. These genes are expressed at higher levels after 48-h sigC induction, but also elevated are genes encoding copper-responsive regulator RicR and RicR-regulated copper toxicity response operon genes rv0846–rv0850, suggesting prolonged sigC induction results in excessive copper uptake. No growth and global transcriptional differences are observed between a sigC null mutant relative to its parent strain in 7H9 medium. In a copper-deficient medium, however, growth of the sigC deletion strain lags the parent, and 40 genes (including those in the nrp operon) are differentially expressed. Copper supplementation reverses the growth defect and silences most transcriptional differences. Together, these data support SigC as a transcriptional regulator of copper acquisition when the metal is scarce. Attenuation of sigC mutants in severe combined immunodeficient mice is consistent with an inability to overcome innate host defenses that sequester copper ions to deprive invading microbes of this essential micronutrient.
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Hahn, Mi-Young, Sahadevan Raman, Mauricio Anaya, and Robert N. Husson. "The Mycobacterium tuberculosis Extracytoplasmic-Function Sigma Factor SigL Regulates Polyketide Synthases and Secreted or Membrane Proteins and Is Required for Virulence." Journal of Bacteriology 187, no. 20 (2005): 7062–71. http://dx.doi.org/10.1128/jb.187.20.7062-7071.2005.
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ABSTRACT Mycobacterium tuberculosis sigL encodes an extracytoplasmic function (ECF) sigma factor and is adjacent to a gene for a membrane protein (Rv0736) that contains a conserved HXXXCXXC sequence. This motif is found in anti-sigma factors that regulate several ECF sigma factors, including those that control oxidative stress responses. In this work, SigL and Rv0736 were found to be cotranscribed, and the intracellular domain of Rv0736 was shown to interact specifically with SigL, suggesting that Rv0736 may encode an anti-sigma factor of SigL. An M. tuberculosis sigL mutant was not more susceptible than the parental strain to several oxidative and nitrosative stresses, and sigL expression was not increased in response to these stresses. In vivo, sigL is expressed from a weak SigL-independent promoter and also from a second SigL-dependent promoter. To identify SigL-regulated genes, sigL was overexpressed and microarray analysis of global transcription was performed. Four small operons, sigL (Rv0735)-Rv0736, mpt53 (Rv2878c)-Rv2877c, pks10 (Rv1660)-pks7 (Rv1661), and Rv1139c-Rv1138c, were among the most highly upregulated genes in the sigL-overexpressing strain. SigL-dependent transcription start sites of these operons were mapped, and the consensus promoter sequences TGAACC in the −35 region and CGTgtc in the −10 region were identified. In vitro, purified SigL specifically initiated transcription from the promoters of sigL, mpt53, and pks10. Additional genes, including four PE_PGRS genes, appear to be regulated indirectly by SigL. In an in vivo murine infection model, the sigL mutant strain showed marked attenuation, indicating that the sigL regulon is important in M. tuberculosis pathogenesis.
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Safi, Hassan, Pooja Gopal, Subramanya Lingaraju, et al. "Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance." Proceedings of the National Academy of Sciences 116, no. 39 (2019): 19665–74. http://dx.doi.org/10.1073/pnas.1907631116.
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The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.