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Mycobacterium bovis BCG-Mediated Protection against W-Beijing Strains of Mycobacterium tuberculosis Is Diminished Concomitant with the Emergence of Regulatory T Cells

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682.
Clinical and vaccine Immunology: CVI (Impact Factor: 2.47). 07/2011; 18(9):1527-35. DOI: 10.1128/CVI.05127-11
Source: PubMed

ABSTRACT

Despite issues relating to variable efficacy in the past, the Mycobacterium bovis BCG vaccine remains the basis for new-generation recombinant vaccines currently in clinical trials. To date, vaccines have been tested mostly against laboratory strains and not against the newly emerging clinical strains. In this study, we evaluated the ability of BCG Pasteur to protect mice from aerosol infections with two highly virulent W-Beijing clinical strains, HN878 and SA161. In a conventional 30-day protection assay, BCG was highly protective against both strains, but by day 60 of the assay, this protection was diminished. Histological examination of the lungs of vaccinated animals showed reduced lung consolidation and smaller and more-organized granulomas in the vaccinated mice after 30 days, but in both cases, these tissues demonstrated worsening pathology over time. Effector T cell responses were increased in the vaccinated mice infected with HN878, but these diminished in number after day 30 of the infections concomitant with increased CD4(+) Foxp3(+) T cells in the lungs, draining lymph nodes, and the spleen. Given the concomitant decrease in effector immunity and continued expansion of regulatory Foxp3(+) cells observed here, it is reasonable to hypothesize that downregulation of effector immunity by these cells may be a serious impediment to the efficacy of BCG-based vaccines.

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Available from: Marcela I Henao-Tamayo
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    • "Further experiments are needed to determine whether it is possible to keep the effector response sustained and stable and to elucidate the factors that differentiate the outcome of T reg depletion in vaccinated and nonvaccinated, M. tuberculosis-infected mice. To directly investigate the role of T regs generated in BCGvaccinated M. tuberculosis-infected mice and infected-only mice, we transferred lymphocytes enriched for T regs into recipients infected with virulent Beijing strains, either HN878 or SA161, because they induced similar results in our model[13]. We first needed to demonstrate that these cells could migrate to the lung in Rag2 2/2 mice after intravenous transfer. "
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    ABSTRACT: Increasing information has shown that many newly emerging strains of Mycobacterium tuberculosis, including the highly prevalent and troublesome Beijing family of strains, can potently induce the emergence of Foxp3(+) CD4 Tregs. Although the significance of this is still not fully understood, we have previously provided evidence that the emergence of this population can significantly ablate the protective effect of BCG vaccination, causing progressive fatal disease in the mouse model. However, whether the purpose of this response is to control inflammation or to directly dampen the acquired immune response is still unclear. In the present study, we have shown, using both cell depletion and adoptive transfer strategies, that Tregs can have either properties. Cell depletion resulted in a rapid, but transient, decrease in the lung bacterial load, suggesting release or temporary re-expansion of effector immunity. Transfer of Tregs into Rag2(-/-) or marked congenic mice worsened the disease course and depressed cellular influx of effector T cells into the lungs. Tregs from infected donors seemed to preferentially depress the inflammatory response and granulocytic influx. In contrast, those from BCG-vaccinated and then challenged donors seemed more focused on depression of acquired immunity. These qualitative differences might be related to increasing knowledge reflecting the plasticity of the Treg response.
    Full-text · Article · Nov 2015 · Journal of Leukocyte Biology
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    • "The causes behind the vaccine's poor performance are unclear, but may include exposure to environmental mycobacteria [4], variable and reduced efficacy of different BCG strains [5] [6], or variation in the infecting M. tuberculosis strain. In particular, the BCG vaccine has been found to be less effective against the widespread M. tuberculosis Beijing family [7] [8], members of which have been associated with increased levels of virulence and drug resistance [9]. These troubling statistics highlight the urgent need for new, more effective vaccines against TB. "
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    ABSTRACT: Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), infects over two billion people, claiming around 1.5 million lives annually. The only vaccine approved for clinical use against this disease is the Bacillus Calmette-Guérin (BCG) vaccine. Unfortunately, BCG has limited efficacy against the adult, pulmonary form of tuberculosis. This vaccine was developed from M. bovis with antigen expression and host specificity that differ from M. tuberculosis. To address these problems, we have designed two novel, live attenuated vaccine (LAV) candidates on an M. tuberculosis background: ΔmosR and ΔechA7. These targeted genes are important to M. tuberculosis pathogenicity during infection. To examine the efficacy of these strains, C57BL/6 mice were vaccinated subcutaneously with either LAV, BCG, or PBS. Both LAV strains persisted up to 16 weeks in the spleens or lungs of vaccinated mice, while eliciting minimal pathology prior to challenge. Following challenge with a selected, high virulence M. tuberculosis Beijing strain, protection was notably greater for both groups of LAV vaccinated animals as compared to BCG at both 30 and 60 days post-challenge. Additionally, vaccination with either ΔmosR or ΔechA7 elicited an immune response similar to BCG. Although these strains require further development to meet safety standards, this first evidence of protection by these two new, live attenuated vaccine candidates shows promise.
    Full-text · Article · Sep 2015 · Vaccine
    • "The role of Foxp3 þ regulatory T cells may be even more pronounced during infection with hypervirulent strains of Mtb such as the W-Beijing strains (Shang et al. 2011). There is also evidence that the hyperinduction of Tregs during infections with W-Beijing strains of Mtb may overcome much of the protective effects of BCG vaccination (Ordway et al. 2011). Therefore, signals from regulatory T cells inhibit the priming of Mtb-specific CD4 T cells and may limit their function in the periphery, and they directly contribute to the inability of the host to clear Mtb infection. "
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    ABSTRACT: Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the coordinated efforts of innate and adaptive immune cells. Diverse pulmonary myeloid cell populations respond to Mtb with unique contributions to both host-protective and potentially detrimental inflammation. Although multiple cell types of the adaptive immune system respond to Mtb infection, CD4 T cells are the principal antigen-specific cells responsible for containment of Mtb infection, but they can also be major contributors to disease during Mtb infection in several different settings. Here, we will discuss the role of different myeloid populations as well as the dual nature of CD4 T cells in Mtb infection with a primary focus on data generated using in vivo cellular immunological studies in experimental animal models and in humans when available. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    No preview · Article · Jul 2015 · Cold Spring Harbor Perspectives in Medicine
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