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


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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    • "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.
    Vaccine 09/2015; 33(42). DOI:10.1016/j.vaccine.2015.08.084 · 3.62 Impact Factor
    • "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.
    Cold Spring Harbor Perspectives in Medicine 07/2015; DOI:10.1101/cshperspect.a018424 · 9.47 Impact Factor
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    • "After infection with Mtb, Tregs are not only present in lymphoid organs, but are also recruited to lung granulomas in a TLR2-dependent manner [9], [13]. Likewise, Treg expansion has been also observed upon M. bovis Bacille Calmette-Guerin (BCG) vaccination and there is evidence that Tregs may correlate with the poor efficiency of this vaccine strain in conferring protection from pulmonary Tb [14], [15]. Particularly, BCG efficacy is lower in developing countries, where people are continuously exposed to low levels of environmental mycobacteria or helminth infections, both associated with high number of circulating Tregs [16], [17]. "
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    ABSTRACT: The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.
    PLoS ONE 07/2014; 9(7):e102804. DOI:10.1371/journal.pone.0102804 · 3.23 Impact Factor
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