Long‐Term Persistence of BCG Pasteur in Lungs of C57BL/6 Mice Following Intranasal Infection

Leversen, Nils Anders; Sviland, Lisbet; Wiker, Harald G.; Mustafa, Tehmina

doi:10.1111/j.1365-3083.2012.02683.x

Cited by 15 publications

(9 citation statements)

References 39 publications

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“…Analysis of total virus particles in batches of Ad-TB10.4 & Ad-empty revealed no differences, and therefore does not explain this differential effect. It is known that Ad vectors induce innate responses [34], and data demonstrate BCG to persist long after vaccination [35][36][37]. Combined with previous reports [38][39][40], we propose the Ad vector is adjuvanting persistent BCG, enhancing specific immune responses.…”

Section: Discussionmentioning

confidence: 54%

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Kaveh¹,

García-Pelayo²,

Webb³

et al. 2016

Vaccine

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Boosting BCG using heterologous prime-boost represents a promising strategy for improved tuberculosis (TB) vaccines, and adenovirus (Ad) delivery is established as an efficacious boosting vehicle. Although studies demonstrate that intranasal administration of Ad boost to BCG offers optimal protection, this is not currently possible in cattle. Using Ad vaccine expressing the mycobacterial antigen TB10.4 (BCG/Ad-TB10.4), we demonstrate, parenteral boost of BCG immunised mice to induce specific CD8(+) IFN-γ producing T cells via synergistic priming of new epitopes. This induces significant improvement in pulmonary protection against Mycobacterium bovis over that provided by BCG when assessed in a standard 4week challenge model. However, in a stringent, year-long survival study, BCG/Ad-TB10.4 did not improve outcome over BCG, which we suggest may be due to the lack of additional memory cells (IL-2(+)) induced by boosting. These data indicate BCG-prime/parenteral-Ad-TB10.4-boost to be a promising candidate, but also highlight the need for further understanding of the mechanisms of T cell priming and associated memory using Ad delivery systems. That we were able to generate significant improvement in pulmonary protection above BCG with parenteral, rather than mucosal administration of boost vaccine is critical; suggesting that the generation of effective mucosal immunity is possible, without the risks and challenges of mucosal administration, but that further work to specifically enhance sustained protective immunity is required.

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Section: Discussionmentioning

confidence: 54%

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Kaveh¹,

García-Pelayo²,

Webb³

et al. 2016

Vaccine

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“…The question of BCG persistence has been noted in previous studies in mice [24,25,27,[32][33][34][35], other animal models [23,26] and humans [36,37]. In a similar study using C57BL/6 mice and M. tb challenge [27], spleen protection was reduced by 75%, but in contrast lung immunity was unaffected.…”

Section: Discussionmentioning

confidence: 72%

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

Kaveh

García-Pelayo

Hogarth

2014

Vaccine

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Tuberculosis (TB) remains one of the most important infectious diseases of man and animals, and the only available vaccine (BCG) requires urgent replacement or improvement. To facilitate this, the protective mechanisms induced by BCG require further understanding. As a live attenuated vaccine, persistence of BCG bacilli in the host may be a crucial mechanism. We have investigated the long term persistence of BCG following vaccination and the influence on the induced immune response and protection, using an established murine model. We sought to establish whether previously identified BCG-specific CD4 TEM cells represent genuine long-lived memory cells of a relatively high frequency, or are a consequence of continual priming by chronically persistent BCG vaccine bacilli. By clearing persistent bacilli, we have compared immune responses (spleen and lung CD4: cytokine producing T effector/TEM; TCR-specific) and BCG-induced protection, in the presence and absence of these persisting vaccine bacilli. Viable BCG bacilli persisted for at least 16 months post-vaccination, associated with specific CD4 T effector/TEM and tetramer-specific responses. Clearing these bacilli abrogated all BCG-specific CD4 T cells whilst only reducing protection by 1log10. BCG may induce two additive mechanisms of immunity: (i) dependant on the presence of viable bacilli and TEM; and (ii) independent of these factors. These data have crucial implications on the rational generation of replacement TB vaccines, and the interpretation of BCG induced immunity in animal models.

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“…25 Intranasal (IN) infection of mice with M. bovis BCG induces pulmonary pathology in the form of cellular infiltration of macrophages and lymphocytes. 20,28 We examined how these lung pathologies are affected by co-infection. Co-infection with M. bovis BCG at day 5 (early) post Nb infection showed a trend for increased Nb-induced alveolar dilation ( Figure 2).…”

Section: Bcg Infection At Day 5 Post Nb Infection Reduces Pulmonary Mmentioning

confidence: 99%

Acute helminth infection enhances early macrophage mediated control of mycobacterial infection

et al. 2013

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Co-infection with mycobacteria and helminths is widespread in developing countries, but how this alters host immunological control of each pathogen is not comprehensively understood. In this study, we demonstrate that acute Nippostrongylus brasiliensis (Nb) murine infection reduce early pulmonary mycobacterial colonization. This Nb-associated reduction in pulmonary Mycobacterium tuberculosis colony-forming units was associated with early and increased activation of pulmonary CD4 T cells and increased T helper type 1 (Th1) and Th2 cytokine secretion. An accelerated and transient augmentation of neutrophils and alveolar macrophages (AMs) was also observed in co-infected animals. AMs displayed markers of both classical and alternative activation. Intranasal transfer of pulmonary macrophages obtained from donor mice 5 days after Nb infection significantly reduced pulmonary Mycobacterium bovis Bacille Calmette-Guérin clearance in recipient mice. These data demonstrate that early stage Nb infection elicits a macrophage response, which is protective during the early stages of subsequent mycobacterial infection.

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Long‐Term Persistence of BCG Pasteur in Lungs of C57BL/6 Mice Following Intranasal Infection

Cited by 15 publications

References 39 publications

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Persistent BCG bacilli perpetuate CD4 T effector memory and optimal protection against tuberculosis

Acute helminth infection enhances early macrophage mediated control of mycobacterial infection

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