Abstract
The antigen-specific Th17 responses in the lungs for improved immunity against Mycobacterium tuberculosis (Mtb) infection are incompletely understood. Tuberculosis (TB) vaccine candidate HSP90-ESAT-6 (E6), given as a Bacillus Calmette-Guérin (BCG)-prime boost regimen, confers superior long-term protection against the hypervirulent Mtb HN878 infection, compared to BCG or BCG-E6. Taking advantage of protective efficacy lead-out, we found that ESAT-6-specific multifunctional CD4+IFN-γ+IL-17+ T-cells optimally correlated with protection level against Mtb infection both pre-and post-challenge. Macrophages treated with the supernatant of re-stimulated lung cells from HSP90-E6-immunised mice significantly restricted Mtb growth, and this phenomenon was abrogated by neutralising anti-IFN-γ and/or anti-IL-17 antibodies. We identified a previously unrecognised role for IFN-γ/IL-17 synergism in linking anti-mycobacterial phagosomal activity to enhance host control against Mtb infection. The implications of our findings highlight the fundamental rationale for why and how Th17 responses are essential in the control of Mtb, and for the development of novel anti-TB subunit vaccines.
Highlights
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is associated with high morbidity and mortality, posing a global public health problem
We previously demonstrated that a subunit vaccine consisting of the ESAT-6 Mtb antigen fused with HSP90 formulated with MPL/dimethyldioctadecyl- ammonium (DDA) as an adjuvant confers high-level, robust protection against the hypervirulent Beijing strain, HN878 [10]
All Ag-specific Th1 cytokines, except IL-4 and IL-10, were significantly induced in mice immunised with ESAT-6 or HSP90-E6 when compared to mice immunised with Bacillus Calmette-Guérin (BCG) alone (Figure 1b,c)
Summary
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is associated with high morbidity and mortality, posing a global public health problem. Approximately 1.7 billion people, 23% of the global population, are estimated to have latent. TB infection and to be at risk of developing active TB during their lifetime. The emergence of Mtb strains resistant to TB drugs poses a major growing burden of hard-to-treat infections [2]. Antigen (Ag) targets, and vaccine platforms have been developed in an aim to improve Mtb vaccines. These efforts have yielded various results, with some producing positive outcomes in clinical trials.
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