scholarly journals Influence of Mycobacterium bovis BCG Vaccination on Cellular Immune Response of Guinea Pigs Challenged with Mycobacterium tuberculosis

2008 ◽  
Vol 15 (8) ◽  
pp. 1248-1258 ◽  
Author(s):  
Diane Ordway ◽  
Marcela Henao-Tamayo ◽  
Crystal Shanley ◽  
Erin E. Smith ◽  
Gopinath Palanisamy ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Lung Damage ◽  
Cell Populations ◽  
Lung Pathology ◽  
Bcg Vaccination ◽  
Macrophage Populations ◽  
Cellular Immune

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG) currently remains the only licensed vaccine for the prevention of tuberculosis. In this study, we used a newly described flow cytometric technique to monitor changes in cell populations accumulating in the lungs and lymph nodes of naïve and vaccinated guinea pigs challenged by low-dose aerosol infection with virulent Mycobacterium tuberculosis. As anticipated, vaccinated guinea pigs controlled the growth of the challenge infection more efficiently than controls did. This early phase of bacterial control in immune animals was associated with increased accumulation of CD4 and CD8 T cells, including cells expressing the activation marker CD45, as well as macrophages expressing class II major histocompatibility complex molecules. As the infection continued, the numbers of T cells in the lungs of vaccinated animals waned, whereas the numbers of these cells expressing CD45 increased. Whereas BCG vaccination reduced the influx of heterophils (neutrophils) into the lungs, an early B-cell influx was observed in these vaccinated animals. Overall, vaccine protection was associated with reduced pathology and lung damage in the vaccinated animals. These data provide the first direct evidence that BCG vaccination accelerates the influx of protective T-cell and macrophage populations into the infected lungs, diminishes the accumulation of nonprotective cell populations, and reduces the severity of lung pathology.

scholarly journals Differential Expression of Gamma Interferon mRNA Induced by Attenuated and Virulent Mycobacterium tuberculosis in Guinea Pig Cells after Mycobacterium bovis BCG Vaccination

2003 ◽  
Vol 71 (1) ◽  
pp. 354-364 ◽  
Author(s):  
Amminikutty Jeevan ◽  
Teizo Yoshimura ◽  
Kyeong Eun Lee ◽  
David N. McMurray
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Lymph Node ◽  
Amino Acid ◽  
Guinea Pig ◽  
Mrna Expression ◽  
Mycobacterium Bovis ◽  
Bcg Vaccination ◽  
Lymph Node Cells ◽  
Ifn Γ

ABSTRACT To determine whether Mycobacterium bovis BCG vaccination would alter gamma interferon (IFN-γ) mRNA expression in guinea pig cells exposed to Mycobacterium tuberculosis, we cloned a cDNA encoding guinea pig IFN-γ from a spleen cell cDNA library. The cDNA is composed of 1,110 bp, with an open reading frame encoding a 166-amino-acid protein which shows 56 and 41% amino acid sequence homology to human and mouse IFN-γ, respectively. Spleen or lymph node cells from naïve and BCG-vaccinated guinea pigs were stimulated with purified protein derivative (PPD) or M. tuberculosis H37Ra or H37Rv, and the total RNA was subjected to Northern blot analysis with a 32P-labeled probe derived from the cDNA clone. Compared to the IFN-γ mRNA expression in cells of naïve animals, that in spleen and lymph node cells exposed to various stimuli was enhanced after BCG vaccination. However, there was a significant reduction in IFN-γ mRNA levels when cells were stimulated with a multiplicity of infection of greater than 1 virulent M. tuberculosis bacterium per 10 cells. The enhanced IFN-γ mRNA response in BCG-vaccinated animals was associated with an increase in the proportions of CD4+ T cells in the spleens, as determined by fluorescence-activated cell sorter analysis. Furthermore, the nonadherent population in the spleens enriched either by panning with anti-guinea pig immunoglobulin G-coated plates or by purification on nylon wool columns produced more IFN-γ mRNA than whole spleen cells following stimulation with concanavalin A or PPD. This indicates that T cells are principally responsible for the upregulation of IFN-γ mRNA expression following BCG vaccination. The mechanism by which virulent mycobacteria suppress IFN-γ mRNA accumulation is currently under investigation.

Mycobacterium bovis BCG vaccination modulates TNF-α production after pulmonary challenge with virulent Mycobacterium tuberculosis in guinea pigs

Tuberculosis ◽  
2007 ◽  
Vol 87 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Toshiko Yamamoto ◽  
Todd M. Lasco ◽  
Kazuyuki Uchida ◽  
Yoshitaka Goto ◽  
Amminikutty Jeevan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Mycobacterium Bovis Bcg ◽  
Bcg Vaccination ◽  
Tnf Α

scholarly journals The Protective Effect of the Mycobacterium bovis BCG Vaccine Is Increased by Coadministration with the Mycobacterium tuberculosis 72-Kilodalton Fusion Polyprotein Mtb72F in M. tuberculosis-Infected Guinea Pigs

2004 ◽  
Vol 72 (11) ◽  
pp. 6622-6632 ◽  
Author(s):  
Lise Brandt ◽  
Yasir A. W. Skeiky ◽  
Mark R. Alderson ◽  
Yves Lobet ◽  
Wilfried Dalemans ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Guinea Pig ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Airway Remodeling ◽  
Bacterial Load ◽  
Bcg Vaccine ◽  
Protective Capacity ◽  
Bcg Vaccination ◽  
Lung Consolidation

ABSTRACT A tuberculosis vaccine candidate consisting of a 72-kDa polyprotein or fusion protein based upon the Mtb32 and Mtb39 antigens of Mycobacterium tuberculosis and designated Mtb72F was tested for its protective capacity as a potential adjunct to the Mycobacterium bovis BCG vaccine in the mouse and guinea pig models of this disease. Formulation of recombinant Mtb72F (rMtb72F) in an AS02A adjuvant enhanced the Th1 response to BCG in mice but did not further reduce the bacterial load in the lungs after aerosol challenge infection. In the more stringent guinea pig disease model, rMtb72F delivered by coadministration with BCG vaccination significantly improved the survival of these animals compared to BCG alone, with some animals still alive and healthy in their appearance at >100 weeks post-aerosol challenge. A similar trend was observed with guinea pigs in which BCG vaccination was boosted by DNA vaccination, although this increase was not statistically significant due to excellent protection conferred by BCG alone. Histological examination of the lungs of test animals indicated that while BCG controls eventually died from overwhelming lung consolidation, the majority of guinea pigs receiving BCG mixed with rMtb72F or boosted twice with Mtb72F DNA had mostly clear lungs with minimal granulomatous lesions. Lesions were still prominent in guinea pigs receiving BCG and the Mtb72F DNA boost, but there was considerable evidence of lesion healing and airway remodeling and reestablishment. These data support the hypothesis that the coadministration or boosting of BCG vaccination with Mtb72F may limit the lung consolidation seen with BCG alone and may promote lesion resolution and healing. Collectively, these data suggest that enhancing BCG is a valid vaccination strategy for tuberculosis that is worthy of clinical evaluation.

scholarly journals Vaccination of Guinea Pigs with DNA Encoding the Mycobacterial Antigen MPB83 Influences Pulmonary Pathology but Not Hematogenous Spread following Aerogenic Infection with Mycobacterium bovis

2002 ◽  
Vol 70 (4) ◽  
pp. 2159-2165 ◽  
Author(s):  
Mark A. Chambers ◽  
Ann Williams ◽  
Graham Hatch ◽  
Dolores Gavier-Widén ◽  
Graham Hall ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Vaccination Strategy ◽  
Control Program ◽  
Dna Vaccination ◽  
Mycobacterial Antigen ◽  
Lung Pathology ◽  
Dna Encoding ◽  
Hematogenous Spread ◽  
Bcg Vaccination

ABSTRACT Protection of cattle against bovine tuberculosis by vaccination could be an important control strategy in countries where there is persistent Mycobacterium bovis infection in wildlife and in developing countries where it is not economical to implement a tuberculin test and slaughter control program. The main aim of such a vaccination strategy would be to reduce transmission of infection by reducing the lung pathology caused by infection and preventing seeding of the organism to organs from which M. bovis could be excreted. Recent reports of successful DNA vaccination against Mycobacterium tuberculosis in small-animal models have suggested that DNA vaccines act by reducing lung pathology without sensitizing animals to tuberculin testing. We therefore evaluated the ability of vaccines consisting of DNA encoding the mycobacterial antigens MPB83 and 85A to reduce lung pathology and prevent hematogenous spread in guinea pigs challenged with a low dose of aerosolized M. bovis. Vaccination with MPB83 DNA reduced the severity of pulmonary lesions, as assessed by histopathology, and resembled M. bovis BCG vaccination in this respect. However, unlike BCG vaccination, MPB83 DNA vaccination did not protect challenged guinea pigs from hematogenous spread of organisms to the spleen. In contrast, vaccination with antigen 85A DNA, a promising DNA vaccine for human tuberculosis, had no measurable protective effect against infection with M. bovis.

scholarly journals Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination with Mycobacterium bovis BCG and Infection with Mycobacterium tuberculosis

2009 ◽  
Vol 77 (11) ◽  
pp. 4837-4846 ◽  
Author(s):  
Ajay Grover ◽  
Jennifer Taylor ◽  
JoLynn Troudt ◽  
Andrew Keyser ◽  
Kimberly Arnett ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Mycobacterium Bovis ◽  
T Cell Activation ◽  
Guinea Pigs ◽  
Cell Activation ◽  
Activated T Cells ◽  
Bcg Vaccination ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, since Mycobacterium bovis BCG vaccination effectively prolongs survival after low-dose aerosol infection with virulent M. tuberculosis. To better understand how BCG extends time to death after pulmonary infection with M. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+ CD62Llow and CD8+ CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+ CD62Llow T cells at day 40, although the numbers of CD8+ CD62Llow T cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.

scholarly journals Influence of Advanced Age on Mycobacterium bovis BCG Vaccination in Guinea Pigs Aerogenically Infected with Mycobacterium tuberculosis

2010 ◽  
Vol 17 (10) ◽  
pp. 1500-1506 ◽  
Author(s):  
Shihoko Komine-Aizawa ◽  
Toshio Yamazaki ◽  
Tsuyoshi Yamazaki ◽  
Shin-ichiro Hattori ◽  
Yuji Miyamoto ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Public Health Problem ◽  
Booster Vaccination ◽  
The Elderly ◽  
Major Public Health Problem ◽  
Bcg Vaccination ◽  
Ifn Γ ◽  
Mycobacterial Antigens

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only tuberculosis (TB) vaccine currently available, but its efficacy against adult pulmonary TB remains controversial. BCG induces specific immune responses to mycobacterial antigens and may elicit protective immunity against TB. TB remains a major public health problem, especially among the elderly, yet the efficacy of BCG in the elderly is unknown. We investigated the ability of BCG vaccination to prevent TB in young (6-week-old), middle-aged (18-month-old), and old (60-month-old) guinea pigs. BCG-Tokyo vaccination reduced the growth of Mycobacterium tuberculosis H37Rv in all three groups. By use of an enzyme-linked immunospot (ELISPOT) assay, antigen-specific gamma interferon (IFN-γ)-producing cells were detected in the 60-month-old guinea pigs after a booster vaccination with BCG-Tokyo. Our findings suggest that BCG-Tokyo has a protective effect against tuberculosis infection regardless of age.

scholarly journals Protection Elicited by Two Glutamine Auxotrophs of Mycobacterium tuberculosis and In Vivo Growth Phenotypes of the Four Unique Glutamine Synthetase Mutants in a Murine Model

2006 ◽  
Vol 74 (11) ◽  
pp. 6491-6495 ◽  
Author(s):  
Sunhee Lee ◽  
Bo-Young Jeon ◽  
Svetoslav Bardarov ◽  
Mei Chen ◽  
Sheldon L. Morris ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Glutamine Synthetase ◽  
Mycobacterium Bovis ◽  
Murine Model ◽  
Triple Mutant ◽  
Auxotrophic Mutants ◽  
Bcg Vaccination ◽  
In Vivo Growth ◽  
Subcutaneous Immunization

ABSTRACT We generated four individual glutamine synthetase (GS) mutants (ΔglnA1, ΔglnA2, ΔglnA3, and ΔglnA4) and one triple mutant (ΔglnA1EA2) of Mycobacterium tuberculosis to investigate the roles of GS enzymes. Subcutaneous immunization with the ΔglnA1EA2 and ΔglnA1 glutamine auxotrophic mutants conferred protection on C57BL/6 mice against an aerosol challenge with virulent M. tuberculosis, which was comparable to that provided by Mycobacterium bovis BCG vaccination.

scholarly journals Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis

Vaccine ◽  
2012 ◽  
Vol 30 (9) ◽  
pp. 1572-1582 ◽  
Author(s):  
Shaobin Shang ◽  
Crystal A. Shanley ◽  
Megan L. Caraway ◽  
Eileen A. Orme ◽  
Marcela Henao-Tamayo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Treatment ◽  
Guinea Pigs ◽  
Bcg Vaccination ◽  
Disease Reactivation

scholarly journals Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques

2015 ◽  
Vol 22 (9) ◽  
pp. 992-1003 ◽  
Author(s):  
A. D. White ◽  
C. Sarfas ◽  
K. West ◽  
L. S. Sibley ◽  
A. S. Wareham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bcg Vaccine ◽  
Effector Memory ◽  
Dependent Manner ◽  
Aerosol Delivery ◽  
Memory Phenotype ◽  
Bcg Vaccination

ABSTRACTNine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, theMycobacterium bovisBCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

scholarly journals Generation of Attenuated Mycobacterium bovis Strains by Signature-Tagged Mutagenesis for Discovery of Novel Vaccine Candidates

2005 ◽  
Vol 73 (4) ◽  
pp. 2379-2386 ◽  
Author(s):  
Desmond M. Collins ◽  
Bronwyn Skou ◽  
Stefan White ◽  
Shalome Bassett ◽  
Lauren Collins ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Guinea Pigs ◽  
Essential Role ◽  
Immunoblot Analysis ◽  
Infection Model ◽  
Vaccine Candidates ◽  
Mouse Infection Model ◽  
Potential Vaccine

ABSTRACT Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex, has a particularly wide host range and causes tuberculosis in most mammals, including humans. A signature tag mutagenesis approach, which employed illegitimate recombination and infection of guinea pigs, was applied to M. bovis to discover genes important for virulence and to find potential vaccine candidates. Fifteen attenuated mutants were identified, four of which produced no lesions when inoculated separately into guinea pigs. One of these four mutants had nine deleted genes including mmpL4 and sigK and, in guinea pigs with aerosol challenge, provided protection against tuberculosis at least equal to that of M. bovis BCG. Seven mutants had mutations near the esxA (esat-6) locus, and immunoblot analysis of these confirmed the essential role of other genes at this locus in the secretion of EsxA (ESAT-6) and EsxB (CFP10). Mutations in the eight other attenuated mutants were widely spread through the chromosome and included pks1, which is naturally inactivated in clinical strains of M. tuberculosis. Many genes identified were different from those found by signature tag mutagenesis of M. tuberculosis by use of a mouse infection model and illustrate how the use of different approaches enables identification of a wider range of attenuating mutants.

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