Journal articles on the topic 'Murine Mycobacterium tuberculosis infection'
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1
Juffermans, Nicole P., Jaklien C. Leemans, Sandrine Florquin, Annelies Verbon, Arend H. Kolk, Peter Speelman, Sander J. H. van Deventer, and Tom van der Poll. "CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis." Infection and Immunity 70, no. 1 (January 2002): 147–52. http://dx.doi.org/10.1128/iai.70.1.147-152.2002.
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ABSTRACT Oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs activate immune cells to produce cytokines. CpG ODNs protect mice against infections with intracellular bacteria by the induction of a T helper 1 (Th1) response. To determine the effect of CpG ODNs in pulmonary tuberculosis, mice were treated with CpG ODNs or control ODNs at the time of intranasal infection. CpG ODNs reduced mycobacterial outgrowth for up to 5 weeks after Mycobacterium tuberculosis infection and were associated with a decrease in inflammation in lung tissue. CpG treatment was also associated with elevated levels of gamma interferon (IFN-γ) and decreased levels of interleukin 4 in the lungs and an increased capacity of splenocytes to secrete Th1-type cytokines. CpG ODNs given 2 weeks after infection were still able to reduce mycobacterial outgrowth and to enhance a Th1 response 5 weeks postinfection. Administration of CpG ODNs to IFN-γ-gene-deficient mice failed to reduce mycobacterial outgrowth. These data suggest that CpG ODNs improve host defense during pulmonary tuberculosis by an IFN-γ-dependent mechanism.
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Gilpin, Trey E. "Migration Kinetics and Migratory Morphology of Mycobacterium-Infected CD11c-eYFP Murine Bone Marrow Derived Cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 102.12. http://dx.doi.org/10.4049/jimmunol.200.supp.102.12.
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Abstract Central nervous system tuberculosis (CNSTB) is the most serious manifestation of extrapulmonary tuberculosis infections that represent 5–10% of all cases. Although migration of mycobacterium infected cells from the lung to the CNS is critical in bacterial dissemination into the CNS, very little is known about the migratory phenotypic changes of mycobacterium infected cells and overall the mechanism of dissemination into the brain is poorly understood. Mycobacterium tuberculosis is an obligate pathogenic bacterial species with it’s only mode of transportation being within innate immune cells. Dendritic cells (DCs) are potent antigen presenting cells that migrate long distances and through interactions with T-cells, initiate the adaptive immune response. Our lab has previously shown DCs are able to leave Mycobacterial granulomatous lesions from the lung with bacteria intact. Here we used live cell imaging of an under-agarose migration assay and cell tracking to define the kinetics of CD11c-eYFP DC migration during Mycobacterial infection. We found that migration of mycobacterium infected cells was impaired towards CCL19 chemokine and infected cells portrayed a migratory morphology distinct from uninfected DCs. With the use of CD11c-eYFP-LifeAct-RFP reporter mice, we characterized actin polymerization dynamics within infected CD11c cells. As actin polymerization plays a central role in cell migration, morphology, and pathogen internalization, to understand this process during mycobacterial infection will lead to novel therapeutic therapies to modulate dissemination into the CNS.
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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 (March 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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Quiding-Järbrink, Marianne, Debbie A. Smith, and Gregory J. Bancroft. "Production of Matrix Metalloproteinases in Response to Mycobacterial Infection." Infection and Immunity 69, no. 9 (September 1, 2001): 5661–70. http://dx.doi.org/10.1128/iai.69.9.5661-5670.2001.
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ABSTRACT Matrix metalloproteinases (MMPs) constitute a large family of enzymes with specificity for the various proteins of the extracellular matrix which are implicated in tissue remodeling processes and chronic inflammatory conditions. To investigate the role of MMPs in immunity to mycobacterial infections, we incubated murine peritoneal macrophages with viable Mycobacterium bovis BCG or Mycobacterium tuberculosis H37Rv and assayed MMP activity in the supernatants by zymography. Resting macrophages secreted only small amounts of MMP-9 (gelatinase B), but secretion increased dramatically in a dose-dependent manner in response to either BCG or M. tuberculosis in vitro. Incubation with mycobacteria also induced increased MMP-2 (gelatinase A) activity. Neutralization of tumor necrosis alpha (TNF-α), and to a lesser extent interleukin 18 (IL-18), substantially reduced MMP production in response to mycobacteria. Exogenous addition of TNF-α or IL-18 induced macrophages to express MMPs, even in the absence of bacteria. The immunoregulatory cytokines gamma interferon (IFN-γ), IL-4, and IL-10 all suppressed BCG-induced MMP production, but through different mechanisms. IFN-γ treatment increased macrophage secretion of TNF-α but still reduced their MMP activity. Conversely, IL-4 and IL-10 seemed to act by reducing the amount of TNF-α available to the macrophages. Finally, infection of BALB/c or severe combined immunodeficiency (SCID) mice with either BCG or M. tuberculosis induced substantial increases in MMP-9 activity in infected tissues. In conclusion, we show that mycobacterial infection induces MMP-9 activity both in vitro and in vivo and that this is regulated by TNF-α, IL-18, and IFN-γ. These findings indicate a possible contribution of MMPs to tissue remodeling processes that occur in mycobacterial infections.
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Stokes, R. W., and D. P. Speert. "Lipoarabinomannan inhibits nonopsonic binding of Mycobacterium tuberculosis to murine macrophages." Journal of Immunology 155, no. 3 (August 1, 1995): 1361–69. http://dx.doi.org/10.4049/jimmunol.155.3.1361.
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Abstract The initial phagocytic interaction between Mycobacterium tuberculosis and macrophages (M phi) in the lung is probably nonopsonic, which would mean that M phi receptors will bind directly to bacterial ligands without the involvement of serum opsonins. Lipoarabinomannan (LAM) is a major component of the cell wall of mycobacteria. The possibility that LAM is involved in the nonopsonic binding of M. tuberculosis to M phi was investigated by using competitive inhibition assays. LAM inhibited binding of M. tuberculosis to murine peritoneal M phi in a dose-dependent manner. LAM also inhibited the binding of Mycobacterium avium and Mycobacterium bovis BCG to M phi. Phosphatidylinositol mannoside and lipomannan have the same phosphatidylinositol (PI) moiety as LAM, but differ in their glycosylation patterns. Both molecules inhibited binding of M. tuberculosis to M phi. Deacylation of LAM abrogated its capacity to inhibit binding of M. tuberculosis to M phi. These observations indicated that it was the PI moiety of LAM that was important in mediating its inhibitory properties. In support of this hypothesis, commercial PI was shown to inhibit the binding of M. tuberculosis to M phi. Our results suggest that cellfree LAM is able to inhibit the binding of mycobacteria to M phi, but that it does not do so by competing with any interaction between M phi receptors and cell-associated LAM, because the PI end of the molecule is believed to be anchored in the bacterial plasma membrane, and therefore not available as a ligand on the cell surface. However, LAM that is released from M. tuberculosis in the course of its active replication during infection may be able to interfere with the phagocytic clearance of mycobacteria.
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Snewin, Valerie A., Marie-Pierre Gares, Peadar ÓGaora, Zahra Hasan, Ivor N. Brown, and Douglas B. Young. "Assessment of Immunity to Mycobacterial Infection with Luciferase Reporter Constructs." Infection and Immunity 67, no. 9 (September 1, 1999): 4586–93. http://dx.doi.org/10.1128/iai.67.9.4586-4593.1999.
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ABSTRACT Protective immunity to mycobacterial infection is incompletely understood but probably involves the coordinated interaction of multiple cell types and cytokines. With the aim of developing assays that might provide a surrogate measure of protective immunity, we have investigated the use of recombinant mycobacteria carrying luciferase reporter enzymes to assess the effectiveness of antimycobacterial immunity in model systems. Measurement of luminescence was shown to provide a rapid and simple alternative to the counting of CFU as a means of monitoring mycobacterial viability. We describe optimization of a luciferase reporter strain of Mycobacterium tuberculosis and demonstrate its application for the study of mycobacterial interactions with host cells in tissue culture and the rapid assessment of vaccine efficacy in a murine model.
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Linnemann, Lara C., Ulrich E. Schaible, and Tobias K. Dallenga. "Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo." International Journal of Molecular Sciences 23, no. 5 (February 25, 2022): 2554. http://dx.doi.org/10.3390/ijms23052554.
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Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.
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Randall, Philippa J., Nai-Jen Hsu, Dirk Lang, Susan Cooper, Boipelo Sebesho, Nasiema Allie, Roanne Keeton, et al. "Neurons Are Host Cells for Mycobacterium tuberculosis." Infection and Immunity 82, no. 5 (February 24, 2014): 1880–90. http://dx.doi.org/10.1128/iai.00474-13.
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ABSTRACTMycobacterium tuberculosisinfection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions ofM. tuberculosiswith neuronsin vitroandin vivowere investigated. The data obtained demonstrate that neurons can act as host cells forM. tuberculosis.M. tuberculosisbacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization ofM. tuberculosisbacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalizeM. tuberculosis. InternalizedM. tuberculosisbacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h.M. tuberculosisbacillus infection of neurons was confirmedin vivoin the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells forM. tuberculosiswithin the central nervous system.
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Manabe, Yukari C., Cherise P. Scott, and William R. Bishai. "Naturally Attenuated, Orally Administered Mycobacterium microti as a Tuberculosis Vaccine Is Better than Subcutaneous Mycobacterium bovis BCG." Infection and Immunity 70, no. 3 (March 2002): 1566–70. http://dx.doi.org/10.1128/iai.70.3.1566-1570.2002.
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ABSTRACT Mycobacterium microti is phylogenetically closely related to Mycobacterium tuberculosis and is a member of that complex of organisms. It is a curved, acid-fast bacillus that is naturally attenuated with a narrow host range for Microtus species only. In this study, we confirm the unique susceptibility of voles to infection with M. microti and the relative resistance of mice with a significantly lower organism burden after 8 weeks of infection. In addition, histopathologic examination of lungs reveals a lack of cellular, granulomatous aggregates characteristically seen in murine M. tuberculosis infection. In the past, M. microti has been used successfully in humans as a vaccine against tuberculosis but was associated with cutaneous reactions. In an attempt to circumvent this adverse effect, we report the efficacy of aerosol and oral vaccination with M. microti. High-dose orogastric vaccination with M. microti resulted in a statistically significant improvement in protection against aerosol challenge with virulent M. tuberculosis in the murine model compared with subcutaneous M. bovis BCG Pasteur vaccination.
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Moreira, Andre L., Liana Tsenova, Melles Haile Aman, Linda-Gail Bekker, Sherry Freeman, Bande Mangaliso, Ulf Schröder, et al. "Mycobacterial Antigens Exacerbate Disease Manifestations in Mycobacterium tuberculosis-Infected Mice." Infection and Immunity 70, no. 4 (April 2002): 2100–2107. http://dx.doi.org/10.1128/iai.70.4.2100-2107.2002.
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ABSTRACT To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-α, and to a lesser extent, IL-2 and gamma interferon (IFN-γ), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-α resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-α-induced inflammation without reducing the bacillary load.
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Pasula, Rajamouli, Paul Wisniowski, and William J. Martin. "Fibronectin Facilitates Mycobacterium tuberculosis Attachment to Murine Alveolar Macrophages." Infection and Immunity 70, no. 3 (March 2002): 1287–92. http://dx.doi.org/10.1128/iai.70.3.1287-1292.2002.
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ABSTRACT Mycobacterium tuberculosis remains a major cause of pulmonary infection worldwide. Attachment of M. tuberculosis organisms to alveolar macrophages (AMs) represents the earliest phase of primary infection in pulmonary tuberculosis. In this study fibronectin (Fn), an adhesive protein, is shown to bind M. tuberculosis organisms and facilitates attachment of M. tuberculosis to murine AMs. A monoclonal antibody (MAb) specific to the heparin binding domain (HBD) of Fn decreases 125I-Fn binding to M. tuberculosis; whereas MAbs specific to either the cell binding domain (CBD) or the gelatin binding domain (GBD) have no effect on Fn binding to M. tuberculosis. In the presence of exogenous Fn (10 μg/ml) M. tuberculosis attachment to AMs increased significantly from control levels (means ± standard errors of the means) of 11.5% ± 1.1% to 44.2% ± 4.2% (P < 0.05). Fn-enhanced attachment was significantly decreased from 44.2% ± 4.2% to 10.8% ± 1.2% (P < 0.05) in the presence of anti-Fn polyclonal antibodies. The attachment is also inhibited in the presence of MAbs specific for the HBD and CBD, whereas MAbs specific to GBD did not affect the attachment. Further, an Fn cell binding peptide, Arg-Gly-Asp-Ser (RGDS), decreased the attachment from 44.2% ± 4.2% to 15.3% ± 1.2% (P < 0.05), whereas addition of a control peptide, Arg-Gly-Glu-Ser (RGES) did not affect the attachment (40.5% ± 1.8%). These results suggest that Fn-mediated attachment of M. tuberculosis can occur through the binding of Fn to the AM via the CBD and to M. tuberculosis organisms via the HBD.
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Mason, Carol M., Elizabeth Dobard, Ping Zhang, and Steve Nelson. "Alcohol Exacerbates Murine Pulmonary Tuberculosis." Infection and Immunity 72, no. 5 (May 2004): 2556–63. http://dx.doi.org/10.1128/iai.72.5.2556-2563.2004.
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ABSTRACT Alcohol consumption has been described as a risk factor for infection with Mycobacterium tuberculosis, but its contribution to tuberculosis has been difficult to isolate from other adverse socioeconomic factors. Our objective was to evaluate the impact of alcohol consumption on pulmonary infection with M. tuberculosis in a murine model. BALB/c mice were maintained on the Lieber-DeCarli liquid ethanol diet or a liquid control diet and infected intratracheally with low-dose M. tuberculosis H37Rv. Lung organism burdens, lung and lung-associated lymph node CD4+- and CD8+- lymphocyte numbers and rates of proliferation, and CD4+-lymphocyte cytokine production levels were compared between the groups. The alcohol-consuming mice had significantly higher lung organism burdens than the control mice, and the CD4+- and CD8+-lymphocyte responses to pulmonary infection with M. tuberculosis were blunted in the alcohol group. Lymphocyte proliferation and production of gamma interferon were decreased in the CD4+ lymphocytes from the alcohol-consuming mice. Additionally, lung granulomas were significantly smaller in the alcohol-consuming mice. In conclusion, murine alcohol consumption is associated with decreased control of pulmonary infection with M. tuberculosis, which is accompanied by alterations in the region-specific CD4+- and CD8+-lymphocyte responses and defective lung granuloma formation.
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Bodnar, Kendra A., Natalya V. Serbina, and JoAnne L. Flynn. "Fate of Mycobacterium tuberculosis within Murine Dendritic Cells." Infection and Immunity 69, no. 2 (February 1, 2001): 800–809. http://dx.doi.org/10.1128/iai.69.2.800-809.2001.
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ABSTRACT The interaction of microbes with dendritic cells (DCs) is likely to have an enormous impact on the initiation of the immune response against a pathogen. In this study, we compared the interaction ofMycobacterium tuberculosis with murine bone marrow-derived DCs and macrophages (Mφ) in vitro. M. tuberculosis grew equally well within nonactivated DCs and Mφ. Activation of DCs and Mφ with gamma interferon and lipopolysaccharide inhibited the growth of the intracellular bacteria in a nitric oxide synthase-dependent fashion. However, while this activation enabled Mφ to kill the intracellular bacteria, the M. tuberculosis bacilli within activated DCs were not killed. Thus, DCs could restrict the growth of the intracellular mycobacteria but were less efficient than Mφ at eliminating the infection. These results may have implications for priming immune responses to M. tuberculosis. In addition, they suggest that DCs may serve as a reservoir for M. tuberculosis in tissues, including the lymph nodes and lungs.
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Talaat, Adel M., Sarah K. Ward, Chia-Wei Wu, Elizabeth Rondon, Christine Tavano, John P. Bannantine, Rick Lyons, and Stephen A. Johnston. "Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling." Journal of Bacteriology 189, no. 11 (March 23, 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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Cynamon, M. H., Y. Zhang, T. Harpster, S. Cheng, and M. S. DeStefano. "High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine Mycobacterium tuberculosis Infection." Antimicrobial Agents and Chemotherapy 43, no. 12 (December 1, 1999): 2922–24. http://dx.doi.org/10.1128/aac.43.12.2922.
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ABSTRACT The use of isoniazid (INH) for the treatment of INH-resistantMycobacterium tuberculosis infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptibleM. tuberculosis Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body weight) was more effective than standard-dose INH (25 mg/kg) for therapy of tuberculosis infections caused by INH-resistant mutants of M. tuberculosisErdman. Six-week-old CD-1 mice were infected with approximately 107 viable mycobacteria. Early control groups of infected but untreated mice were euthanized by CO2 inhalation 1 week later when treatment was initiated. INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week for 4 weeks. Late control groups of untreated mice and treated mice were sacrificed 2 days after the last dose of drug. Spleens and right lungs were removed aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates. In the next study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic mutant of M. tuberculosis Erdman (INH MIC, 2 μg/ml) and the parent strain. This mutant was found to have a mutation in the KatG protein (Phe to Leu at position 183). In the first study, there was no dose response with increasing doses of INH. In the second study, there was no significant difference between the reduction of viable cell counts for mice treated with INH at 100 mg/kg and that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant). These preliminary results suggest that INH may be useful in combination therapy of M. tuberculosis infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 μg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose.
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Domenech, Pilar, Hajime Kobayashi, Kristin LeVier, Graham C. Walker, and Clifton E. Barry. "BacA, an ABC Transporter Involved in Maintenance of Chronic Murine Infections with Mycobacterium tuberculosis." Journal of Bacteriology 191, no. 2 (November 7, 2008): 477–85. http://dx.doi.org/10.1128/jb.01132-08.
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ABSTRACT BacA is an inner membrane protein associated with maintenance of chronic infections in several diverse host-pathogen interactions. To understand the function of the bacA gene in Mycobacterium tuberculosis (Rv1819c), we insertionally inactivated this gene and analyzed the resulting mutant for a variety of phenotypes. BacA deficiency in M. tuberculosis did not affect sensitivity to detergents, acidic pH, and zinc, indicating that there was no global compromise in membrane integrity, and a comprehensive evaluation of the major lipid constituents of the cell envelope failed to reveal any significant differences. Infection of mice with this mutant revealed no impact on establishment of infection but a profound effect on maintenance of extended chronic infection and ultimate outcome. As in alphaproteobacteria, deletion of BacA in M. tuberculosis led to increased bleomycin resistance, and heterologous expression of the M. tuberculosis BacA homolog in Escherichia coli conferred sensitivity to antimicrobial peptides. These results suggest a striking conservation of function for BacA-related proteins in transport of a critical molecule that determines the outcome of the host-pathogen interaction.
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Scanga, Charles A., Vellore P. Mohan, Kathryn Tanaka, David Alland, JoAnne L. Flynn, and John Chan. "The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice." Infection and Immunity 69, no. 12 (December 1, 2001): 7711–17. http://dx.doi.org/10.1128/iai.69.12.7711-7717.2001.
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ABSTRACT Murine macrophages effect potent antimycobacterial function via the production of nitric oxide by the inducible isoform of the enzyme nitric oxide synthase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosisinfection has been well established in various murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. However, important questions remain about the in vivo importance of RNI in host defense against M. tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous,M. tuberculosis infection of mice. Furthermore, in vitro studies have demonstrated that different strains of M. tuberculosis, including clinical isolates, vary widely in their susceptibility to the antimycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates of M. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique M. tuberculosis strains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrupted mice. Regardless of the route of infection, NOS2−/− mice were much more susceptible than wt mice to any of the clinical isolates or to either the Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replicated to much higher levels in the organs of NOS2−/− mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence in NOS2−/− mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the control of murine tuberculous infection caused by both laboratory and clinical strains of M. tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.
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Flynn, JoAnne L., Charles A. Scanga, Kathryn E. Tanaka, and John Chan2. "Effects of Aminoguanidine on Latent Murine Tuberculosis." Journal of Immunology 160, no. 4 (February 15, 1998): 1796–803. http://dx.doi.org/10.4049/jimmunol.160.4.1796.
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Abstract A unique feature of Mycobacterium tuberculosis is its ability to establish latent infection in the human host, which can reactivate to cause disease years later. In the present study, the mechanisms involved in the control of latent tuberculous infection were examined using two murine experimental tuberculosis models. Analysis of the model involving infection of mice with a relatively low inoculum of the virulent Erdman strain of M. tuberculosis indicated that in vivo inhibition of reactive nitrogen intermediate (RNI) production by the nitric oxide synthase inhibitor aminoguanidine resulted in reactivation. This reactivation was evidenced by hepatosplenomegaly, a robust tissue granulomatous reaction, and increased bacillary load. IFN-γ, TNF-α, and inducible nitric oxide synthase were all expressed throughout the latent phase of infection. Reactivation of latent tuberculous infection by aminoguanidine treatment was confirmed using a second murine tuberculosis model based on treatment with antimycobacterial drugs. Results obtained using this drug-based model also suggested the existence of an RNI-independent antimycobacterial mechanism(s) operative in the latent phase of infection. Together, these data suggest that both RNI-dependent and -independent mechanisms contribute to the prevention of tuberculous reactivation.
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Navoa, Josephine Anne D., Suman Laal, Liise-Anne Pirofski, Gary R. McLean, Zhongdong Dai, John B. Robbins, Rachel Schneerson, Arturo Casadevall, and Aharona Glatman-Freedman. "Specificity and Diversity of Antibodies to Mycobacterium tuberculosis Arabinomannan." Clinical Diagnostic Laboratory Immunology 10, no. 1 (January 2003): 88–94. http://dx.doi.org/10.1128/cdli.10.1.88-94.2003.
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ABSTRACT Arabinomannan (AM) is a polysaccharide antigen of the mycobacterial capsule. However, it is uncertain whether AM constitutes an immunologically distinct fraction of Mycobacterium tuberculosis. In this study, we analyzed the repertoire and specificity of antibodies to AM by using AM-binding murine monoclonal antibodies (MAbs) and human serum samples. Murine MAbs were found to be diverse in their specificity to AM and cross-reactivity with other arabinose-containing mycobacterial polysaccharides, with MAb 9d8 binding exclusively to AM. Human antibodies to AM were detected in serum samples from patients with pulmonary tuberculosis (TB), as well as in those from healthy, purified protein derivative-negative controls, with significantly higher titers among patients. The binding of human antibodies to AM was inhibited by MAb 9d8 in three patients with TB but not in controls. MAb 5c11, which recognizes other mycobacterial arabinose-containing carbohydrates in addition to AM, inhibited the binding of serum samples from 75% of patients and 76% of controls. Analysis of human antibodies with murine MAbs to human VH determinants demonstrated diversity among antibodies to AM with qualitative and quantitative differences compared with antibodies to lipoarabinomannan. In summary, our study suggests that antibodies to AM are diverse and heterogeneous with respect to antigen recognition and VH determinant expression, with human serum samples containing different subsets of antibodies to AM with the specificities of AM-binding murine MAbs. One MAb and a subset of human antibodies bind AM specifically, suggesting that this polysaccharide is antigenically distinct and is expressed in human infection.
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Fulton, Scott A., Scott M. Reba, Rish K. Pai, Meghan Pennini, Martha Torres, Clifford V. Harding, and W. Henry Boom. "Inhibition of Major Histocompatibility Complex II Expression and Antigen Processing in Murine Alveolar Macrophages by Mycobacterium bovis BCG and the 19-Kilodalton Mycobacterial Lipoprotein." Infection and Immunity 72, no. 4 (April 2004): 2101–10. http://dx.doi.org/10.1128/iai.72.4.2101-2110.2004.
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ABSTRACT Alveolar macrophages constitute a primary defense against Mycobacterium tuberculosis, but they are unable to control M. tuberculosis without acquired T-cell immunity. This study determined the antigen-presenting cell function of murine alveolar macrophages and the ability of the model mycobacterium, Mycobacterium bovis BCG, to modulate it. The majority (80 to 85%) of alveolar macrophages expressed both CD80 (B7.1) and CD11c, and 20 to 30% coexpressed major histocompatibility complex II (MHC-II). Gamma interferon (IFN-γ) enhanced MHC-II but not B7.1 expression. Naive or IFN-γ-treated alveolar macrophages did not express CD86 (B7.2), CD11b, Mac-3, CD40, or F4/80. M. bovis BCG and the 19-kDa mycobacterial lipoprotein inhibited IFN-γ-regulated MHC-II expression on alveolar macrophages, and inhibition was dependent on Toll-like receptor 2. The inhibition of MHC-II expression by the 19-kDa lipoprotein was associated with decreased presentation of soluble antigen to T cells. Thus, susceptibility to tuberculosis may result from the ability of mycobacteria to interfere with MHC-II expression and antigen presentation by alveolar macrophages.
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Ignatov, D. V., O. Yu Timoshina, N. N. Logunova, T. A. Skvortsov, and T. L. Azhikina. "Expression of small RNAs of Mycobacterium tuberculosis in murine models of tuberculosis infection." Russian Journal of Bioorganic Chemistry 40, no. 2 (March 2014): 233–35. http://dx.doi.org/10.1134/s1068162014020058.
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O'Riordan, Katie, David S. Sharlin, Jerome Gross, Sung Chang, Divya Errabelli, Oleg E. Akilov, Sachiko Kosaka, Gerard J. Nau, and Tayyaba Hasan. "Photoinactivation of Mycobacteria In Vitro and in a New Murine Model of Localized Mycobacterium bovis BCG-Induced Granulomatous Infection." Antimicrobial Agents and Chemotherapy 50, no. 5 (May 2006): 1828–34. http://dx.doi.org/10.1128/aac.50.5.1828-1834.2006.
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ABSTRACT Treatment of tuberculosis is currently hindered by prolonged antibiotic regimens and the emergence of significant drug resistance. Alternatives and adjuncts to standard antimycobacterial agents are needed. We propose that a direct attack utilizing photosensitizers and light-based treatments may be effective in curtailing Mycobacterium tuberculosis in discrete anatomical sites in the most infectious phase of pulmonary tuberculosis. To demonstrate experimental proof of principle, we have applied established photodynamic therapy (PDT) technology to in vitro cultures and an in vivo mouse model using Mycobacterium bovis BCG. We report here in vitro and in vivo PDT efficacy studies and the use of a three-dimensional collagen gel as a delivery vehicle for BCG, subcutaneously inserted, to induce specifically localized granuloma-like lesions in mice. When a benzoporphyrin derivative was utilized as the photosensitive agent, exposure to light killed extracellular and intracellular BCG in significant numbers. Collagen scaffolds containing BCG inserted in situ in BALB/c mice for 3 months mimicked granulomatous lesions and demonstrated a marked cellular infiltration upon histological examination, with evidence of caseating necrosis and fibrous capsule formation. When 105 BCG were present in the in vivo-induced granulomas, a significant reduction in viable mycobacterial cells was demonstrated in PDT-treated granulomas compared to those of controls. We conclude that PDT has potential in the treatment of localized mycobacterial infections, such as pulmonary granulomas and cavities.
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Woodworth, Joshua S., Sarah M. Fortune, and Samuel M. Behar. "Bacterial Protein Secretion Is Required for Priming of CD8+ T Cells Specific for the Mycobacterium tuberculosis Antigen CFP10." Infection and Immunity 76, no. 9 (June 30, 2008): 4199–205. http://dx.doi.org/10.1128/iai.00307-08.
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ABSTRACT Mycobacterium tuberculosis infection elicits antigen-specific CD8+ T cells that are required to control disease. It is unknown how the major histocompatibility complex class I (MHC-I) pathway samples mycobacterial antigens. CFP10 and ESAT6 are important virulence factors secreted by M. tuberculosis, and they are immunodominant targets of the human and murine T-cell response. Here, we test the hypothesis that CFP10 secretion by M. tuberculosis is required for the priming of CD8+ T cells in vivo. Our results reveal an explicit dependence upon the bacterial secretion of the CFP10 antigen for the induction of antigen-specific CD8+ T cells in vivo. By using well-defined M. tuberculosis mutants and carefully controlling for virulence, we show that ESX-1 function is required for the priming of CD8+ T cells specific for CFP10. CD4+ and CD8+ T-cell responses to mycobacterial antigens secreted independently of ESX-1 were unaffected, suggesting that ESX-1-dependent phagosomal escape is not required for CD8+ T-cell priming during infection. We propose that the overrepresentation of secreted proteins as dominant targets of the CD8+ T-cell response during M. tuberculosis infection is a consequence of their preferential sampling by the MHC-I pathway. The implications of these findings should be considered in all models of antigen presentation during M. tuberculosis infection and in vaccine development.
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Tanne, Antoine, Bo Ma, Frédéric Boudou, Ludovic Tailleux, Hélène Botella, Edgar Badell, Florence Levillain, et al. "A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis." Journal of Experimental Medicine 206, no. 10 (September 21, 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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Henao-Tamayo, Marcela, Andrés Obregón-Henao, Elizabeth Creissen, Crystal Shanley, Ian Orme, and Diane J. Ordway. "Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis." Clinical and Vaccine Immunology 22, no. 1 (November 12, 2014): 91–98. http://dx.doi.org/10.1128/cvi.00466-14.
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ABSTRACTThe global epidemic caused by the bacterial pathogenMycobacterium tuberculosiscontinues unabated. Moreover, the only available vaccine against tuberculosis,Mycobacterium bovisbacillus Calmette-Guérin (BCG), demonstrates variable efficacy. To respond to this global threat, new animal models that mimic the pathological disease process in humans are required for vaccine testing. One new model, susceptible C3Heb/FeJ mice, is similar to human tuberculosis in that these animals are capable of forming necrotic tubercle granulomas, in contrast to resistant C3H/HeOuJ mice. In this study, we evaluated the impact of prior BCG vaccination of C3Heb/FeJ and C3H/HeOuJ mice on exposure to a low-dose aerosol ofMycobacterium tuberculosisW-Beijing strain SA161. Both BCG-vaccinated murine strains demonstrated reduced bacterial loads 25 days after infection compared to controls, indicating vaccine efficacy. However, during chronic infection, vaccine efficacy waned in C3H/HeOuJ but not in C3Heb/FeJ mice. Protection in vaccinated C3Heb/FeJ mice was associated with reduced numbers of CD11b+Gr1+cells, increased numbers of effector and memory T cells, and an absence of necrotic granulomas. BCG vaccine efficacy waned in C3H/HeOuJ mice, as indicated by reduced expression of gamma interferon (IFN-γ) and increased expressions of interleukin-17 (IL-17), IL-10, and Foxp3 by T cells compared to C3Heb/FeJ mice. This is the first murine vaccine model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy.
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Nikonenko, Boris, Venkata M. Reddy, Elena Bogatcheva, Marina Protopopova, Leo Einck, and Carol A. Nacy. "Therapeutic Efficacy of SQ641-NE against Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 58, no. 1 (October 21, 2013): 587–89. http://dx.doi.org/10.1128/aac.01254-13.
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ABSTRACTA phospholipid-based nanoemulsion formulation of SQ641 (SQ641-NE) was active against intracellularMycobacterium tuberculosisin J774A.1 mouse macrophages, although SQ641 by itself was not. Intravenous (i.v.) SQ641-NE was cleared from circulation and reached peak concentrations in lung and spleen in 1 h. In a murine tuberculosis (TB) model, 8 i.v. doses of SQ641-NE at 100 mg/kg of body weight over 4 weeks caused a 1.73 log10CFU reduction ofM. tuberculosisin spleen and were generally bacteriostatic in lungs.
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El-Etr, Sahar H., Selvakumar Subbian, Suat L. G. Cirillo, and Jeffrey D. Cirillo. "Identification of Two Mycobacterium marinum Loci That Affect Interactions with Macrophages." Infection and Immunity 72, no. 12 (December 2004): 6902–13. http://dx.doi.org/10.1128/iai.72.12.6902-6913.2004.
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ABSTRACT Mycobacterium marinum is closely related to Mycobacterium tuberculosis, the cause of tuberculosis in humans. M. marinum has become an important model system for the study of the molecular mechanisms involved in causing tuberculosis in humans. Through molecular genetic analysis of the differences between pathogenic and nonpathogenic mycobacteria, we identified two loci that affect the ability of M. marinum to infect macrophages, designated mel 1 and mel 2. In silico analyses of the 11 putative genes in these loci suggest that mel 1 encodes secreted proteins that include a putative membrane protein and two putative transglutaminases, whereas mel 2 is involved in secondary metabolism or biosynthesis of fatty acids. Interestingly, mel 2 is unique to M. marinum and the M. tuberculosis complex and not present in any other sequenced mycobacterial species. M. marinum mutants with mutations in mel 1 and mel 2, constructed by allelic exchange, are defective in the ability to infect both murine and fish macrophage cell lines. These data suggest that the genes in mel 1 and mel 2 are important for the ability of M. marinum to infect host cells.
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Casali, Nicola, Amy M. White, and Lee W. Riley. "Regulation of the Mycobacterium tuberculosis mce1 Operon." Journal of Bacteriology 188, no. 2 (January 15, 2006): 441–49. http://dx.doi.org/10.1128/jb.188.2.441-449.2006.
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ABSTRACT In the murine model of infection, a Mycobacterium tuberculosis mce1 operon mutant elicits an aberrant granulomatous response, resulting in uncontrolled replication and failure to enter a persistent state. In this study, we demonstrate that the mce1 genes can be transcribed as a 13-gene polycistronic message encompassing Rv0166 to Rv0178. Quantitative reverse transcriptase PCR and immunoblot analyses revealed that the mce1 genes and proteins are expressed during in vitro growth but are significantly down-regulated in intracellular bacilli isolated from murine macrophages. A homologue of the FadR subfamily of GntR transcriptional regulators, Rv0165c (designated Mce1R), lies upstream and is divergently transcribed from the operon. To investigate whether this gene plays a role in regulation of mce1 expression, we created an M. tuberculosis mce1R deletion mutant. There was no difference in expression of mce1 operon genes in Δmce1R compared to expression in the wild type during logarithmic growth in vitro. However, in bacilli isolated from murine macrophages, expression of mce1 genes was significantly higher in Δmce1R. In addition, overexpression of mce1R resulted in repression of the mce1 genes. These data demonstrate that Mce1R is a negative regulator that acts intracellularly to repress expression of the mce1 operon. We propose that Mce1R facilitates balanced temporal expression of the mce1 products required for organized granuloma formation, which is both protective to the host and necessary for the persistence of M. tuberculosis.
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Sullivan, Jaryd R., Andréanne Lupien, Elias Kalthoff, Claire Hamela, Lorne Taylor, Kim A. Munro, T. Martin Schmeing, Laurent Kremer, and Marcel A. Behr. "Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline." PLOS Pathogens 17, no. 10 (October 12, 2021): e1009965. http://dx.doi.org/10.1371/journal.ppat.1009965.
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Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M. abscessus is clinically resistant to the entire regimen of front-line M. tuberculosis drugs, and treatment with antibiotics that do inhibit M. abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M. abscessus. EPT protected zebrafish from lethal M. abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M. abscessus than M. tuberculosis, but crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar residues and dissociation constants. Since EPT-resistant M. abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M. abscessus, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M. abscessus and other mycobacterial infections like tuberculosis.
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Scanga, Charles A., V. P. Mohan, Heather Joseph, Keming Yu, John Chan, and JoAnne L. Flynn. "Reactivation of Latent Tuberculosis: Variations on the Cornell Murine Model." Infection and Immunity 67, no. 9 (September 1, 1999): 4531–38. http://dx.doi.org/10.1128/iai.67.9.4531-4538.1999.
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ABSTRACT Mycobacterium tuberculosis causes active tuberculosis in only a small percentage of infected persons. In most cases, the infection is clinically latent, although immunosuppression can cause reactivation of a latent M. tuberculosis infection. Surprisingly little is known about the biology of the bacterium or the host during latency, and experimental studies on latent tuberculosis suffer from a lack of appropriate animal models. The Cornell model is a historical murine model of latent tuberculosis, in which mice infected with M. tuberculosis are treated with antibiotics (isoniazid and pyrazinamide), resulting in no detectable bacilli by organ culture. Reactivation of infection during this culture-negative state occurred spontaneously and following immunosuppression. In the present study, three variants of the Cornell model were evaluated for their utility in studies of latent and reactivated tuberculosis. The antibiotic regimen, inoculating dose, and antibiotic-free rest period prior to immunosuppression were varied. A variety of immunosuppressive agents, based on immunologic factors known to be important to control of acute infection, were used in attempts to reactivate the infection. Although reactivation of latent infection was observed in all three variants, these models were associated with characteristics that limit their experimental utility, including spontaneous reactivation, difficulties in inducing reactivation, and the generation of altered bacilli. The results from these studies demonstrate that the outcome of Cornell model-based studies depends critically upon the parameters used to establish the model.
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Miki, Keita, Toshi Nagata, Takao Tanaka, Yeung-Hyen Kim, Masato Uchijima, Naoya Ohara, Satoshi Nakamura, Masaji Okada, and Yukio Koide. "Induction of Protective Cellular Immunity against Mycobacterium tuberculosis by Recombinant Attenuated Self-Destructing Listeria monocytogenes Strains Harboring Eukaryotic Expression Plasmids for Antigen 85 Complex and MPB/MPT51." Infection and Immunity 72, no. 4 (April 2004): 2014–21. http://dx.doi.org/10.1128/iai.72.4.2014-2021.2004.
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ABSTRACT We report here the induction of specific protective cellular immunity against Mycobacterium tuberculosis by the employment of vaccination with recombinant attenuated Listeria monocytogenes strains. We constructed self-destructing attenuated L. monocytogenes Δ2 strains carrying eukaryotic expression plasmids for the antigen 85 complex (Ag85A and Ag85B) and for MPB/MPT51 (mycobacterial protein secreted by M. bovis BCG/mycobacterial protein secreted by M. tuberculosis) molecules. Infection of these recombinant bacteria allowed expression of the genes in the J774A.1 murine macrophage cell line. Intraperitoneal vaccination of C57BL/6 mice with these recombinant bacteria was capable of inducing purified protein derivative-specific cellular immune responses, such as foot pad reactions, proliferative responses of splenocytes, and gamma interferon production from splenocytes, suggesting the efficacy of vaccination against mycobacterial infection by use of these recombinant L. monocytogenes strains. Furthermore, intravenous vaccination with recombinant bacteria carrying expression plasmids for Ag85A, Ag85B, or MPB/MPT51 in BALB/c mice elicited significant protective responses, comparable to those evoked by a live Mycobacterium bovis BCG vaccine. Notably, this is the first report to show that MPB/MPT51 is a major protective antigen in addition to Ag85A and Ag85B, which have been reported to be major mycobacterial protective antigens.
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Ramachandra, Lakshmi, Yan Qu, Ying Wang, Colleen J. Lewis, Brian A. Cobb, Kiyoshi Takatsu, W. Henry Boom, George R. Dubyak, and Clifford V. Harding. "Mycobacterium tuberculosis Synergizes with ATP To Induce Release of Microvesicles and Exosomes Containing Major Histocompatibility Complex Class II Molecules Capable of Antigen Presentation." Infection and Immunity 78, no. 12 (September 13, 2010): 5116–25. http://dx.doi.org/10.1128/iai.01089-09.
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ABSTRACT Major histocompatibility complex class II (MHC-II) molecules are released by murine macrophages upon lipopolysaccharide (LPS) stimulation and ATP signaling through the P2X7 receptor. These studies show that infection of macrophages with Mycobacterium tuberculosis or M. bovis strain BCG enhances MHC-II release in synergy with ATP. Shed MHC-II was contained in two distinct organelles, exosomes and plasma membrane-derived microvesicles, which were both able to present exogenous antigenic peptide to T hybridoma cells. Furthermore, microvesicles from mycobacterium-infected macrophages were able to directly present M. tuberculosis antigen (Ag) 85B(241-256)-I-Ab complexes that were generated by the processing of M. tuberculosis Ag 85B in infected cells to both M. tuberculosis-specific T hybridoma cells and naïve P25 M. tuberculosis T-cell receptor (TCR)-transgenic T cells. In the presence of prefixed macrophages, exosomes from mycobacterium-infected macrophages provided weak stimulation to M. tuberculosis-specific T hybridoma cells but not naïve P25 T cells. Thus, infection with M. tuberculosis primes macrophages for the increased release of exosomes and microvesicles bearing M. tuberculosis peptide-MHC-II complexes that may generate antimicrobial T-cell responses.
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Page, Kathleen R., Anne E. Jedlicka, Benjamin Fakheri, Gregory S. Noland, Anup K. Kesavan, Alan L. Scott, Nirbhay Kumar, and Yukari C. Manabe. "Mycobacterium-Induced Potentiation of Type 1 Immune Responses and Protection against Malaria Are Host Specific." Infection and Immunity 73, no. 12 (December 2005): 8369–80. http://dx.doi.org/10.1128/iai.73.12.8369-8380.2005.
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ABSTRACT Malaria and tuberculosis are endemic in many regions of the world, and coinfection with the two pathogens is common. In this study, we examined the effects of long- and short-term infection with Mycobacterium tuberculosis on the course of a lethal form of murine malaria in resistant (C57BL/6) and susceptible (BALB/c) mice. C57BL/6 mice coinfected with M. tuberculosis CDC1551 and Plasmodium yoelii 17XL had a lower peak parasitemia and increased survival compared to mice infected with P. yoelii 17XL alone. Splenic microarray analysis demonstrated potentiation of type 1 immune responses in coinfected C57BL/6 mice, which was especially prominent 5 days after infection with P. yoelii 17XL. Splenocytes from coinfected C57BL/6 mice produced higher levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha than splenocytes from mice infected with either pathogen alone. Interestingly, mycobacterium-induced protection against lethal P. yoelii is mouse strain specific. BALB/c mice were significantly more susceptible than C57BL/6 mice to infection with P. yoelii 17XL and were not protected against lethal malaria by coinfection with M. tuberculosis. In addition, M. tuberculosis did not augment IFN-γ responses in BALB/c mice subsequently infected with P. yoelii 17XL. These data indicate that M. tuberculosis-induced potentiation of type 1 immune responses is associated with protection against lethal murine malaria.
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Byrd, Thomas F., and C. Rick Lyons. "Preliminary Characterization of aMycobacterium abscessus Mutant in Human and Murine Models of Infection." Infection and Immunity 67, no. 9 (September 1, 1999): 4700–4707. http://dx.doi.org/10.1128/iai.67.9.4700-4707.1999.
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ABSTRACT The ability to persist in the host after the establishment of infection is an important virulence determinant for mycobacteria.Mycobacterium abscessus is a rapidly growing mycobacterial species which causes a variety of clinical syndromes in humans. We have obtained a rough, wild-type human clinical isolate of M. abscessus (M. abscessus-R) and a smooth, attenuated mutant(M. abscessus-S) which spontaneously dissociated from the clinical isolate. We have found that M. abscessus-R is able to persist and multiply in a murine pulmonary infection model in contrast to M. abscessus-S, which is rapidly cleared. To understand the basis for this difference, we characterized the behavior of these variants in human tissue culture models of infection. M. abscessus-R is able to persist and multiply in human monocytes, while M. abscessus-S is deficient in this ability. Both of these variants are phagocytized by human monocytes. M. abscessus-R resides in a phagosome typical for pathogenic mycobacteria with a tightly adherent phagosomal membrane. In contrast,M. abscessus-S resides in a “loose” phagosome with the phagosomal membrane separated from the bacterial cell wall. BothM. abscessus variants also have distinctive growth patterns in a recently described fibroblast-mycobacterium microcolony assay, with M. abscessus-R exhibiting growth characteristics similar to those previously reported for virulent M. tuberculosis and M. abscessus-S exhibiting growth characteristics similar to those previously reported for avirulentM. tuberculosis. In both the monocyte infection assay and the murine pulmonary infection model, numerous infected mononuclear phagocyte aggregates develop at sites of M. abscessus-Rinfection, but are absent with M. abscessus-S infection. We conclude that a mutation has occurred in the M. abscessus-Svariant which has altered the ability of this organism to persist and multiply in host cells and that this may be related to the phenotypic changes we have observed in our tissue culture models of infection.
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Repique, Charlene J., Amy Li, Frank M. Collins, and Sheldon L. Morris. "DNA Immunization in a Mouse Model of Latent Tuberculosis: Effect of DNA Vaccination on Reactivation of Disease and on Reinfection with a Secondary Challenge." Infection and Immunity 70, no. 7 (July 2002): 3318–23. http://dx.doi.org/10.1128/iai.70.7.3318-3323.2002.
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ABSTRACT Individuals who are latently infected with Mycobacterium tuberculosis can develop active disease via either endogenous reactivation of the latent bacilli or exogenous reinfection with a second mycobacterial strain. In this study, we investigated whether immunization with a tuberculosis DNA vaccine cocktail that induces significant protective responses in mice could prevent reactivation of disease in a murine latent-tuberculosis model. In addition, we assessed whether DNA vaccination could retard the growth of a secondary aerogenic infection with M. tuberculosis (exogenous reinfection) in latently infected mice. In the reactivation studies, administration of the DNA vaccine combination did not prevent recrudescence of the latent infection after injection of dexamethasone. Moreover, for the reinfection experiments, only a modest decrease in the growth of a secondary M. tuberculosis challenge in DNA-vaccinated animals, compared to controls, was observed 14 and 28 days after the reinfection of previously exposed mice. Interestingly, although proliferation of the secondary challenge was reduced significantly in a nonvaccinated chronic-infection group relative to the naïve controls, the number of bacilli still increased by 500-fold 1 month after the secondary challenge in mice with active tuberculosis. These results indicate that novel immunotherapeutic approaches will be required to prevent reactivation of infection or reinfection of individuals with latent tuberculosis.
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Triccas, James A., Elena Shklovskaya, Joanne Spratt, Anthony A. Ryan, Umaimainthan Palendira, Barbara Fazekas de StGroth, and Warwick J. Britton. "Effects of DNA- and Mycobacterium bovis BCG-Based Delivery of the Flt3 Ligand on Protective Immunity to Mycobacterium tuberculosis." Infection and Immunity 75, no. 11 (August 27, 2007): 5368–75. http://dx.doi.org/10.1128/iai.00322-07.
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ABSTRACT The control of intracellular pathogens such as Mycobacterium tuberculosis is dependent on the activation and maintenance of pathogen-reactive T cells. Dendritic cells (DCs) are the major antigen-presenting cells initiating antimycobacterial T-cell responses in vivo. To investigate if immunization strategies that aim to optimize DC function can improve protective immunity against virulent mycobacterial infection, we exploited the ability of the hematopoietic growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) to expand the number of DCs in vivo. A DNA fusion of the genes encoding murine Flt3L and M. tuberculosis antigen 85B stimulated enhanced gamma interferon (IFN-γ) release by T cells and provided better protection against virulent M. tuberculosis than DNA encoding the single components. Vaccination of mice with a recombinant Mycobacterium bovis BCG strain secreting Flt3L (BCG:Flt3L) led to early expansion of DCs compared to immunization with BCG alone, and this effect was associated with increased stimulation of BCG-reactive IFN-γ-secreting T cells. BCG and BCG:Flt3L provided similar protective efficacies against low-dose aerosol M. tuberculosis; however, immunization of immunodeficient mice revealed that BCG:Flt3L was markedly less virulent than conventional BCG. These results demonstrate the potential of in vivo targeting of DCs to improve antimycobacterial vaccine efficacy.
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Yang, Daqing, Beiyi Liu, Xiaoriu Hou, Delong Jiao, Xueli Li, Liyan Wen, Ping Zhu, and Ning Fu. "Pre-treatment with Mycobacterium avium-derived lipids reduces the macrophage response to interferon γ in BCG-vaccinated mice." Journal of Medical Microbiology 62, no. 7 (July 1, 2013): 980–87. http://dx.doi.org/10.1099/jmm.0.056283-0.
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Mycobacterium bovis Bacille Calmette–Guérin (BCG) is the current vaccine used against Mycobacterium tuberculosis (MTB) infection. However, exposure to environmental pathogens, such as Mycobacterium avium, interferes with the immune response induced by BCG vaccination. How M. avium affects the efficiency of BCG is unclear. In this study, BCG-vaccinated mice pre-treated with M. avium-derived lipids (MALs) showed a higher mycobacterial load and increased infiltration of inflammatory cells compared to control mice treated with Escherichia coli-derived lipids (ELs). Unexpectedly, there were no changes in cell proliferation or IFN-γ levels in spleen cells stimulated with protein purified derivatives (PPD) or heat-inactivated BCG in MALs-treated mice. However, pre-treatment with MALs decreased the bactericidal effect as well as the production of TNF-α and nitric oxide (NO) in murine macrophages from BCG-vaccinated mice stimulated with IFN-γ. These results suggest that MAL pre-treatment dampens the immune response against MTB and that this dampening is associated with a decreased response to IFN-γ stimulation in murine macrophages. T-lymphocyte responses, however, were unaffected.
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Zahrt, Thomas C., and Vojo Deretic. "An Essential Two-Component Signal Transduction System in Mycobacterium tuberculosis." Journal of Bacteriology 182, no. 13 (July 1, 2000): 3832–38. http://dx.doi.org/10.1128/jb.182.13.3832-3838.2000.
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ABSTRACT The bacterial two-component signal transduction systems regulate adaptation processes and are likely to play a role inMycobacterium tuberculosis physiology and pathogenesis. The previous initial characterization of an M. tuberculosis response regulator from one of these systems,mtrA-mtrB, suggested its transcriptional activation during infection of phagocytic cells. In this work, we further characterized the mtrA response regulator fromM. tuberculosis H37Rv. Inactivation ofmtrA on the chromosome of M. tuberculosisH37Rv was possible only in the presence of plasmid-borne functionalmtrA, suggesting that this response regulator is essential for M. tuberculosis viability. In keeping with these findings, expression of mtrA in M. tuberculosis H37Rv was detectable during in vitro growth, as determined by S1 nuclease protection and primer extension analyses of mRNA levels and mapping of transcript 5′ ends. The mtrAgene was expressed differently in virulent M. tuberculosis and the vaccine strain M. tuberculosis var. bovis BCG during infection of macrophages, as determined by monitoring of mtrA-gfp fusion activity. In M. bovis BCG, mtrA was induced upon entry into macrophages. In M. tuberculosis H37Rv, its expression was constitutive and unchanged upon infection of murine or human monocyte-derived macrophages. In conclusion, these results identify mtrA as an essential response regulator gene in M. tuberculosis which is differentially expressed in virulent and avirulent strains during growth in macrophages.
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Weijer, Sebastiaan, Catharina W. Wieland, Sandrine Florquin, and Tom van der Poll. "A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis." Blood 106, no. 8 (October 15, 2005): 2761–68. http://dx.doi.org/10.1182/blood-2004-12-4623.
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AbstractThrombomodulin (TM) plays an essential role in the generation of activated protein C (APC), a mediator with both anticoagulant and anti-inflammatory properties, and is preferentially expressed in lungs. To investigate the role of TM in the coagulant and inflammatory response in the lung during tuberculosis, mice with a mutation in the TM gene (Thbd), which results in a minimal capacity for APC generation (TMpro/pro mice), were intranasally infected with live virulent Mycobacterium tuberculosis. Whereas pulmonary tuberculosis was not associated with activation of coagulation in either wild-type or TMpro/pro mice, 5 weeks after infection TMpro/pro mice displayed an uncontrolled inflammatory response in their lungs, as reflected by higher lung weights, a diminished ability to form well-shaped granulomas, elevated levels of proinflammatory cytokines, and concurrently reduced concentrations of anti-inflammatory cytokines. During a 36-week follow-up after infection with a lower dose of M tuberculosis, 35% of TMpro/pro mice died from week 28 onward versus none of the wild-type mice, and the surviving TMpro/pro mice displayed increased lung inflammation accompanied by higher mycobacterial loads in liver and spleen. These data suggest that a TM mutation that impairs APC generation results in uncontrolled lung inflammation during tuberculosis.
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Chan, J., K. Tanaka, D. Carroll, J. Flynn, and B. R. Bloom. "Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis." Infection and immunity 63, no. 2 (1995): 736–40. http://dx.doi.org/10.1128/iai.63.2.736-740.1995.
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Klemens, S. P., C. A. Sharpe, and M. H. Cynamon. "Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility." Antimicrobial Agents and Chemotherapy 40, no. 1 (January 1996): 14–16. http://dx.doi.org/10.1128/aac.40.1.14.
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The activity of pyrazinamide (PZA) against eight isolates of Mycobacterium tuberculosis in a murine infection model was evaluated. M. tuberculosis isolates with various degrees of in vitro susceptibility to PZA (MIC range, 32 to > 2,048 micrograms/ml) were used. Four-week-old female mice were infected intravenously with approximately 10(7) viable M. tuberculosis organisms. PZA at 150 mg/kg of body weight was started 1 day postinfection and given 5 days/week for 4 weeks. Infected but untreated mice were compared with PZA-treated mice. Mice were sacrificed at the completion of the treatment period, and viable cell counts were determined from homogenates of spleens and right lungs. PZA had activity in the murine test system against M. tuberculosis isolates for which the MICs were < or = 256 micrograms/ml. However, there was an inconsistent correlation between the absolute MICs and the reductions in organ viable cell counts. Studies with drug-resistant M. tuberculosis isolates with an isogenic background would improve evaluation of drug efficacy in the murine test system. Further evaluation of antimycobacterial agents against monodrug-resistant isolates will provide data that will be useful for development of algorithms for treatment of infection with drug-resistant organisms.
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Blackwell, J. M., G. F. Black, C. S. Peacock, E. N. Miller, D. Sibthorpe, D. Gnananandha, J. J. Shaw, et al. "Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 352, no. 1359 (September 29, 1997): 1331–45. http://dx.doi.org/10.1098/rstb.1997.0118.
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In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively ‘scan’ the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes ( Nramp1 ) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north–eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family–based linkage analyses (combined segregation and linkage analysis; sib–pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10–;20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan ( ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H–2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFalpha/beta genes) shows both linkage to, and allelic association with, leprosy per se , but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1 , the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A , SCYA2–5 ) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major , is linked to tuberculosis susceptibility; and (iv) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the ‘mouse–to–man’ strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.
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Gao, Lian-Yong, Richard Groger, Jeffery S. Cox, Stephen M. Beverley, Elise H. Lawson, and Eric J. Brown. "Transposon Mutagenesis of Mycobacterium marinum Identifies a Locus Linking Pigmentation and Intracellular Survival." Infection and Immunity 71, no. 2 (February 2003): 922–29. http://dx.doi.org/10.1128/iai.71.2.922-929.2003.
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ABSTRACT Pathogenic mycobacteria survive and replicate within host macrophages, but the molecular mechanisms involved in this necessary step in the pathogenesis of infection are not completely understood. Mycobacterium marinum has recently been used as a model for aspects of the pathogenesis of tuberculosis because of its close genetic relationship to Mycobacterium tuberculosis and because of similarities in the pathology and course of infection caused by this organism in its natural hosts, fish and frogs, with tuberculosis in humans. In order to advance the utility of the M. marinum model, we have developed efficient transposon mutagenesis of the organism by using a Drosophila melanogaster mariner-based transposon. To determine the efficiency of transposition, we have analyzed pigmentation mutants from the transposon mutant library. In addition to insertions in four known genes in the pathway of pigment biosynthesis, two insertions in novel genes were identified in our mutant library. One of these is in a putative inhibitor of the carotenoid biosynthesis pathway. The second unexpected insertion is in an intergenic region between two genes homologous to Rv2603c and Rv2604c of M. tuberculosis. In addition to a pigmentation defect, this mutant showed increased susceptibility to singlet oxygen and grew poorly in murine macrophages. Complementation with M. tuberculosis genomic DNA encompassing Rv2603c to Rv2606c corrected the pigmentation and growth defects of the mutant. These data demonstrate the utility of mariner-based transposon mutagenesis of M. marinum and that M. marinum can be used to study the function of M. tuberculosis genes involved in intracellular survival and replication.
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Gomes, Maria Salomé, Simon Paul, Andre L. Moreira, Rui Appelberg, Michel Rabinovitch, and Gilla Kaplan. "Survival of Mycobacterium avium andMycobacterium tuberculosis in Acidified Vacuoles of Murine Macrophages." Infection and Immunity 67, no. 7 (July 1, 1999): 3199–206. http://dx.doi.org/10.1128/iai.67.7.3199-3206.1999.
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ABSTRACT Despite the antimicrobial mechanisms of vertebrate phagocytes, mycobacteria can survive within the phagosomes of these cells. These organisms use various strategies to evade destruction, including inhibition of acidification of the phagosome and inhibition of phagosome-lysosome fusion. In contrast to mycobacteria, Coxiella burnetii, the etiologic agent of Q fever, inhabits a spacious acidified intracellular vacuole which is prone to fusion with other vacuoles of the host cell, including phagosomes containing mycobacteria. The Coxiella-infected cell thus provides a unique model for investigating the survival of mycobacteria in an acidified phagosome-like compartment. In the present study, murine bone marrow-derived macrophages were infected with eitherMycobacterium avium or Mycobacterium tuberculosis and then coinfected with C. burnetii. We observed that the majority of phagocytosed mycobacteria colocalized to the C. burnetii-containing vacuole, which maintained its acidic properties. In coinfected macrophages, the growth of M. avium was not impaired following fusion with the acidified vacuole. In contrast, the growth rate of M. tuberculosiswas reduced in acidified vacuoles. These results suggest that although both species of mycobacteria inhibit phagosome-lysosome fusion, they may be differentially susceptible to the toxic effects of the acidic environment in the mature phagolysosome.
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Agre, Neha, Nilesh Tawari, Arundhati Maitra, Antima Gupta, Tulika Munshi, Mariam Degani, and Sanjib Bhakta. "3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria." Antibiotics 9, no. 7 (July 1, 2020): 368. http://dx.doi.org/10.3390/antibiotics9070368.
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In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action.
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Jeon, Bo Young, Steven C. Derrick, JaeHyun Lim, Kristopher Kolibab, Veerabadran Dheenadhayalan, Amy Li Yang, Barry Kreiswirth, and Sheldon L. Morris. "Mycobacterium bovis BCG Immunization Induces Protective Immunity against Nine Different Mycobacterium tuberculosis Strains in Mice." Infection and Immunity 76, no. 11 (August 18, 2008): 5173–80. http://dx.doi.org/10.1128/iai.00019-08.
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ABSTRACT Recent preclinical and epidemiologic studies have suggested that certain Mycobacterium tuberculosis genotypes (in particular, Beijing lineage strains) may be resistant to Mycobacterium bovis BCG vaccine-induced antituberculosis protective immunity. To investigate the strain specificity of BCG-induced protective responses in a murine model of pulmonary tuberculosis, C57BL/6 mice were vaccinated with BCG vaccine and then challenged 2 months later with one of nine M. tuberculosis isolates. Four of these strains were from the W-Beijing lineage (HN878, N4, NHN5, and ChS) while four were non-Beijing-type isolates (C913, CDC1551, NY669, and NY920). As a control, the WHO standard M. tuberculosis Erdman strain was evaluated in these vaccination/challenge experiments. To assess the protective responses evoked by BCG immunization, organ bacterial burdens and lung pathology were assessed in vaccinated and naïve mice at 4, 12, and 20 weeks postchallenge as well as during the day of infection. At 4 weeks after the aerosol challenge with each of these strains, significantly reduced bacterial growth in the lungs and spleens and significantly improved lung pathology were seen in all vaccinated animals compared to naïve controls. After 12 weeks, reduced organ bacterial burdens were detected in vaccinated animals infected with six of nine challenge strains. Although lung CFU values were lower in vaccinated mice for only three of nine groups at 20 weeks postchallenge, significantly decreased lung inflammation was seen in all immunized animals relative to controls at 20 weeks postchallenge. Taken together, these data demonstrate that BCG vaccination protects against infection with diverse M. tuberculosis strains in the mouse model of pulmonary tuberculosis and suggest that strain-specific resistance to BCG-induced protective immunity may be uncommon.
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Kelly, B. P., S. K. Furney, M. T. Jessen, and I. M. Orme. "Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 40, no. 12 (December 1996): 2809–12. http://dx.doi.org/10.1128/aac.40.12.2809.
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As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.
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Ramachandra, Lakshmi, Jamie L. Smialek, Sam S. Shank, Marilyn Convery, W. Henry Boom, and Clifford V. Harding. "Phagosomal Processing of Mycobacterium tuberculosis Antigen 85B Is Modulated Independently of Mycobacterial Viability and Phagosome Maturation." Infection and Immunity 73, no. 2 (February 2005): 1097–105. http://dx.doi.org/10.1128/iai.73.2.1097-1105.2005.
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ABSTRACT Control of Mycobacterium tuberculosis infection requires CD4 T-cell responses and major histocompatibility complex class II (MHC-II) processing of M. tuberculosis antigens (Ags). We have previously demonstrated that macrophages process heat-killed (HK) M. tuberculosis more efficiently than live M. tuberculosis. These observations suggested that live M. tuberculosis may inhibit Ag processing by inhibiting phagosome maturation or that HK M. tuberculosis may be less resistant to Ag processing. In the present study we examined the correlation between M. tuberculosis viability and phagosome maturation and efficiency of Ag processing. Since heat treatment could render M. tuberculosis Ags more accessible to proteolysis, M. tuberculosis was additionally killed by antibiotic treatment and radiation. Processing of HK, live, radiation-killed (RadK), or rifampin-killed (RifK) M. tuberculosis in activated murine bone marrow macrophages was examined by using an I-Ab-restricted T-cell hybridoma cell line (BB7) that recognizes an epitope derived from Ag 85B. Macrophages processed HK M. tuberculosis more rapidly and efficiently than they processed live, RadK, or RifK M. tuberculosis. Live, RadK, and RifK M. tuberculosis cells were processed with similar efficiencies for presentation to BB7 T hybridoma cells. Furthermore, phagosomes containing live or RadK M. tuberculosis expressed fewer M. tuberculosis peptide-MHC-II complexes than phagosomes containing HK M. tuberculosis expressed. Since only live M. tuberculosis was able to prevent acidification of the phagosome, our results suggest that regulation of phagosome maturation does not explain the differences in processing of different forms of M. tuberculosis. These findings suggest that the mechanisms used by M. tuberculosis to inhibit phagosomal maturation differ from the mechanisms involved in modulating phagosome Ag processing.
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Fukui, Masayuki, Masayuki Umemura, and Goro Matsuzaki. "Combined vaccination of subcutaneous BCG and intranasal HBHA with cholera toxin enhances early protective immunity against pulmonary M. tuberculosis infection (VAC7P.972)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 141.17. http://dx.doi.org/10.4049/jimmunol.192.supp.141.17.
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Abstract Effect of Mycobacterium bovis bacille de Calmette et Guérin (BCG) vaccine on preventing adult pulmonary tuberculosis has been reported to be limited. Therefore, development of a novel effective vaccination strategy against pulmonary tuberculosis has become an international research priority. We have previously reported that intranasal administration of a recombinant mycobacterial Ag, heparin-binding heamagglutinin adhesin (HBHA), combined with mucosal adjuvant cholera toxin (CT) into mice enhanced Th1-type immune response and suppressed extrapulmonary bacterial dissemination after M. tuberculosis (Mtb) infection in the lung. Here, we further report effects of the mucosal HBHA+CT vaccine on murine experimental pulmonary Mtb infection. Combination of subcutaneous BCG priming vaccine followed by the mucosal HBHA+CT vaccine as a booster significantly enhanced protective immunity against pulmonary Mtb infection on day 14. The combination of subcutaneous BCG and the mucosal HBHA+CT vaccine was more effective than the BCG vaccine alone in induction of the early protective immunity. Further, the mucosal HBHA+CT vaccine enhanced not only IFN-γ but also IL-17A production by HBHA-specific T cells in the lung after pulmonary Mtb infection. The results indicate that the combination of BCG priming vaccine and mucosal HBHA+CT boosting vaccine might be a good candidate for a new vaccine strategy against pulmonary tuberculosis.
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Wu, Yuqing, Cao Li, Andrea Riehle, Barbara Pollmeier, Erich Gulbins, and Heike Grassmé. "Mycobacterial Infection is Promoted by Neutral Sphingomyelinase 2 Regulating a Signaling Cascade Leading to Activation of β1-Integrin." Cellular Physiology and Biochemistry 51, no. 4 (2018): 1815–29. http://dx.doi.org/10.1159/000495683.
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Background/Aims: Mycobacteria-induced diseases, especially tuberculosis, cause more than 1 million deaths each year, which is higher than any other single bacterial pathogen. Neutral sphingomyelinase 2 (Nsm2) has been implied in many physiological processes and diseases, but the role of Nsm2 in pathogen-host interactions and mycobacterial infections has barely been studied. Methods: We investigated the role of the Nsm2/ceramide system in systemic infection of mice and murine macrophages with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) as a model for mycobacterial infection. For in vitro assays we isolated bone marrow-derived macrophages from Wildtype mice or Nsm2-heterozygous and investigated the role of Nsm2 for macrophage migration/clustering as well as the involvement of p38 mitogen-activated protein kinases (p38K), c-Jun N-terminal kinase (JNK), β1-integrin and Rac1 activity by Western blot and microscopic studies. For in vivo assays we injected mice intravenously with BCG and analyzed infected tissues for the role of Nsm2-mediated activation of β1-integrin in granuloma formation and bacterial burden. Results: Our results reveal that BCG infection of macrophages results in rapid stimulation of Nsm2. Genetic and pharmacological studies demonstrate that Nsm2 stimulates a signaling cascade via p38K and JNK to an activation of surface β1-integrin and Rac1 that leads to the formation of granuloma-like macrophages clusters in vitro and granuloma in vivo. Heterozygosity of Nsm2 in macrophages or antibody-mediated neutralization of active b1-integrin reduced macrophage clusters in vitro and granuloma formation in vivo. Most importantly, Nsm2 heterozygosity or treatment with neutralizing antibodies against β1-integrin protected mice from systemic BCG infections and chronic infections of the liver and spleen. Conclusion: The findings indicate that the Nsm2/ ceramide system plays an important role in systemic infection of mice with mycobacteria by regulating a signaling cascade via p38K, JNK, b1-integrin and Rac1.