scholarly journals Nicotinamide Limits Replication of Mycobacterium tuberculosis and Bacille Calmette-Guérin Within Macrophages

2019 ◽  
Vol 221 (6) ◽  
pp. 989-999
Author(s):  
Jason D Simmons ◽  
Glenna J Peterson ◽  
Monica Campo ◽  
Jenny Lohmiller ◽  
Shawn J Skerrett ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nicotinic Acid ◽  
Mycobacterium Bovis ◽  
Related Compound ◽  
Antimicrobial Properties ◽  
Broth Culture ◽  
Wild Type ◽  
Bacille Calmette Guerin ◽  
Macrophage Function ◽  
Modest Activity

Abstract Novel antimicrobials for treatment of Mycobacterium tuberculosis are needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrict M. tuberculosis replication in addition to their direct antimicrobial properties. Both compounds had modest activity in 7H9 broth, but only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM and the related compound pyrazinamide restricted growth of bacille Calmette-Guérin but not wild-type Mycobacterium bovis, which both lack a functional nicotinamidase/pyrazinamidase (PncA) rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulent M. tuberculosis mutant encoding a deletion in pncA. We conclude that the differential activity of NAM and nicotinic acid on infected macrophages suggests host-specific NAM targets rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-type M. bovis or M. tuberculosis.

scholarly journals Immunogenicity of recombinant Mycobacterium bovis bacille Calmette–Guèrin clones expressing T and B cell epitopes of Mycobacterium tuberculosis antigens

2013 ◽  
Vol 14 (Suppl 1) ◽  
pp. S5 ◽  
Author(s):  
Rohimah Mohamud ◽  
Maryam Azlan ◽  
Daniel Yero ◽  
Nadine Alvarez ◽  
Maria E Sarmiento ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
B Cell ◽  
Mycobacterium Bovis ◽  
Bacille Calmette Guerin ◽  
B Cell Epitopes

scholarly journals Priming by DNA Immunization Augments Protective Efficacy of Mycobacterium bovis Bacille Calmette-Guerin against Tuberculosis

2001 ◽  
Vol 69 (6) ◽  
pp. 4174-4176 ◽  
Author(s):  
Carl G. Feng ◽  
Umaimainthan Palendira ◽  
Caroline Demangel ◽  
Joanne M. Spratt ◽  
Adam S. Malin ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Protective Efficacy ◽  
Mycobacterial Antigen ◽  
Dna Immunization ◽  
Bacille Calmette Guerin

ABSTRACT Sequential immunization with mycobacterial antigen Ag85B-expressing DNA and Mycobacterium bovis bacille Calmette-Guerin (BCG) was more effective than BCG immunization in protecting againstMycobacterium tuberculosis infection. Depletion of the CD8+ T cells in the immunized mice impaired protection in their spleens, indicating that this improved efficacy was partially mediated by CD8+ T cells.

scholarly journals Listeria-Vectored Vaccine Expressing the Mycobacterium tuberculosis 30-Kilodalton Major Secretory Protein via the Constitutively Active prfA* Regulon Boosts Mycobacterium bovis BCG Efficacy against Tuberculosis

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Qingmei Jia ◽  
Barbara Jane Dillon ◽  
Saša Masleša-Galić ◽  
Marcus A. Horwitz
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Interleukin 2 ◽  
Secretory Protein ◽  
Broth Culture ◽  
Listeriolysin O ◽  
Content Type ◽  
Ifn Γ ◽  
Constitutively Active

ABSTRACT A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effective Mycobacterium bovis BCG vaccine. Here we investigate novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein (r30/antigen 85B [Ag85B]) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuated L. monocytogenes vectors, L. monocytogenes ΔactA (LmI), L. monocytogenes ΔactA ΔinlB (LmII), and L. monocytogenes ΔactA ΔinlB prfA* (LmIII), we constructed five rLm30 vaccine candidates expressing r30 linked in frame to the L. monocytogenes listeriolysin O signal sequence and driven by the hly promoter (h30) or linked in frame to the ActA N-terminal 100 amino acids and driven by the actA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm30 expressing r30 via a constitutively active prfA* regulon (rLmIII/a30) expressed the largest amount of r30 in broth culture, all five rLm30 vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting of BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T cells expressing the three cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) (P < 0.001) and splenic and lung CD8+ T cells expressing IFN-γ (P < 0.0001). In mice and guinea pigs, the rLmIII/a30 and rLmI/h30 vaccines were generally more potent booster vaccines than r30 with an adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting of mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolized M. tuberculosis (P < 0.01).

scholarly journals Identification of the Missing trans-Acting Enoyl Reductase Required for Phthiocerol Dimycocerosate and Phenolglycolipid Biosynthesis in Mycobacterium tuberculosis

2007 ◽  
Vol 189 (13) ◽  
pp. 4597-4602 ◽  
Author(s):  
Roxane Siméone ◽  
Patricia Constant ◽  
Christophe Guilhot ◽  
Mamadou Daffé ◽  
Christian Chalut
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mutant Strain ◽  
Mycobacterium Bovis ◽  
Reductase Activity ◽  
Polyketide Synthases ◽  
Type I ◽  
Wild Type ◽  
Enoyl Reductase ◽  
Phthiocerol Dimycocerosates ◽  
Activity Domain

ABSTRACT Phthiocerol dimycocerosates (DIM) and phenolglycolipids (PGL) are functionally important surface-exposed lipids of Mycobacterium tuberculosis. Their biosynthesis involves the products of several genes clustered in a 70-kb region of the M. tuberculosis chromosome. Among these products is PpsD, one of the modular type I polyketide synthases responsible for the synthesis of the lipid core common to DIM and PGL. Bioinformatic analyses have suggested that this protein lacks a functional enoyl reductase activity domain required for the synthesis of these lipids. We have identified a gene, Rv2953, that putatively encodes an enoyl reductase. Mutation in Rv2953 prevents conventional DIM formation and leads to the accumulation of a novel DIM-like product. This product is unsaturated between C-4 and C-5 of phthiocerol. Consistently, complementation of the mutant with a functional pks15/1 gene from Mycobacterium bovis BCG resulted in the accumulation of an unsaturated PGL-like substance. When an intact Rv2953 gene was reintroduced into the mutant strain, the phenotype reverted to the wild type. These findings indicate that Rv2953 encodes a trans-acting enoyl reductase that acts with PpsD in phthiocerol and phenolphthiocerol biosynthesis.

scholarly journals Fluoroquinolone Action against Clinical Isolates ofMycobacterium tuberculosis: Effects of a C-8 Methoxyl Group on Survival in Liquid Media and in Human Macrophages

1999 ◽  
Vol 43 (3) ◽  
pp. 661-666 ◽  
Author(s):  
Ben Yang Zhao ◽  
Richard Pine ◽  
John Domagala ◽  
Karl Drlica
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Lethal Dose ◽  
Clinical Isolates ◽  
Methoxyl Group ◽  
Human Macrophage ◽  
Wild Type ◽  
Liquid Media ◽  
Human Macrophages ◽  
Resistant Strains

ABSTRACT When the lethal action of a C-8 methoxyl fluoroquinolone against clinical isolates of Mycobacterium tuberculosis in liquid medium was measured, the compound was found to be three to four times more effective (as determined by measuring the 90% lethal dose) than a C-8-H control fluoroquinolone or ciprofloxacin against cells having a wild-type gyrA (gyrase) gene. Against ciprofloxacin-resistant strains, the C-8 methoxyl group enhanced lethality when alanine was replaced by valine at position 90 of the GyrA protein or when aspartic acid 94 was replaced by glycine, histidine, or tyrosine. During infection of a human macrophage model by wild-type Mycobacterium bovis BCG, the C-8 methoxyl group lowered survival 20- to 100-fold compared with the same concentration of a C-8-H fluoroquinolone. The C-8 methoxyl fluoroquinolone was also more effective than ciprofloxacin against a gyrA Asn94 mutant of M. bovis BCG. In an M. tuberculosis-macrophage system the C-8 methoxyl group improved fluoroquinolone action against both quinolone-susceptible and quinolone-resistant clinical isolates. Thus, a C-8 methoxyl group enhances the bactericidal activity of quinolones with N1-cyclopropyl substitutions; these data encourage further refinement of fluoroquinolones as antituberculosis agents.

scholarly journals Comparison of the Protective Efficacy of Bacille Calmette-Guérin Vaccination against Aerosol Challenge with Mycobacterium tuberculosis and Mycobacterium bovis

2000 ◽  
Vol 30 (Supplement_3) ◽  
pp. S299-S301 ◽  
Author(s):  
Ann Williams ◽  
Angela Davies ◽  
Philip D. Marsh ◽  
Mark A. Chambers ◽  
R. Glyn Hewinson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Protective Efficacy ◽  
Bacille Calmette Guerin

scholarly journals A Mycobacterium tuberculosis Mutant Lacking the groEL Homologue cpn60.1 Is Viable but Fails To Induce an Inflammatory Response in Animal Models of Infection

2008 ◽  
Vol 76 (4) ◽  
pp. 1535-1546 ◽  
Author(s):  
Yanmin Hu ◽  
Brian Henderson ◽  
Peter A. Lund ◽  
Peter Tormay ◽  
M. Tabish Ahmed ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Animal Models ◽  
Inflammatory Response ◽  
Granulomatous Inflammation ◽  
Broth Culture ◽  
Wild Type ◽  
Increased Sensitivity ◽  
Granulomatous Response

ABSTRACT The causative agent of tuberculosis, Mycobacterium tuberculosis, has two chaperonin (Cpn60) proteins and one cochaperonin (Cpn10) protein. We show here that cpn60.2 and cpn10, but not cpn60.1, are essential for cell survival. A mutant lacking Cpn60.1 was indistinguishable from the wild-type organism in plate and broth culture and within murine macrophages, although it showed increased sensitivity to high temperature (55°C). However, infection of mice with the Δcpn60.1 mutant revealed a major difference from the wild-type organism. In spite of having equal numbers of bacteria in infected sites, the Δcpn60.1 mutant failed to produce granulomatous inflammation in either mice or guinea pigs. This was associated with reduced cytokine expression in infected animals and macrophages. Cell wall lipid acid composition was not altered in the mutant strain. Thus, it appears that Cpn60.1 is an important agent in the regulation of the cytokine-dependent granulomatous response in M. tuberculosis infection.

scholarly journals A Human Challenge Model for Mycobacterium tuberculosis Using Mycobacterium bovis Bacille Calmette-Guérin

2012 ◽  
Vol 205 (7) ◽  
pp. 1035-1042 ◽  
Author(s):  
Angela M. Minassian ◽  
Iman Satti ◽  
Ian D. Poulton ◽  
Joel Meyer ◽  
Adrian V. S. Hill ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Bacille Calmette Guerin

scholarly journals Comparative Transcriptional Study of the Putative Mannose Donor Biosynthesis Genes in Virulent Mycobacterium tuberculosis and Attenuated Mycobacterium bovis BCG Strains

2011 ◽  
Vol 79 (11) ◽  
pp. 4668-4673 ◽  
Author(s):  
Tracy L. Keiser ◽  
Abul K. Azad ◽  
Evelina Guirado ◽  
Robert Bonacci ◽  
Larry S. Schlesinger
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Broth Culture ◽  
Biosynthesis Pathway ◽  
Regulation Of Expression ◽  
Content Type ◽  
Expression Levels ◽  
Genes Encoding ◽  
Recognition And Response

ABSTRACTMycobacterium tuberculosiscontains mannosylated cell wall components which are important in macrophage recognition and response. The building block for the mannosyl constituents of these components is GDP-mannose, which is synthesized through a series of enzymes involved in the mannose donor biosynthesis pathway. Nothing is known about the expression levels of the genes encoding these enzymes during the course of infection. To generate transcriptional profiles for the mannose donor biosynthesis genes from virulentM. tuberculosisand attenuatedMycobacterium bovisBCG, bacteria were grown in broth culture and within human macrophages. Our results with broth-grown bacteria show that there are differences in expression of the selected genes betweenM. tuberculosisand BCG, with increased expression ofmanCinM. tuberculosisandmanAin BCG during stationary-phase growth. Results forM. tuberculosisextracted from within macrophages show thatwhiB2is highly expressed andmanBandmanCare moderately expressed during infection.Rv3256c,Rv3258c, andppm1have high expression levels early and decreased expression as the infection progresses. Results with BCG show that, as inM. tuberculosis,whiB2is highly expressed throughout infection, whereas there is either low expression or little change in expression of the remaining genes studied. Overall, our results show that there is differential regulation of expression of several genes in the mannose donor biosynthesis pathway ofM. tuberculosisand BCG grown in broth and within macrophages, raising the possibility that the level of mannose donors may vary during the course of infection and thereby impact the biosynthesis of mannose-containing cell wall molecules.

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