Abstract
Low-dose tolerance using heat-killed mycobacteria has been tested as a means of stopping progression toward active tuberculosis (TB) lesions in a human-like murine model using C3HeB/FeJ mice. In the present study, we studied the effect of different treatment schedules with heat-killed non-tuberculous-mycobacteria (NTM) species when given orally, based on the hypothesis of generating oral tolerance. This study included M. manresensis, a new species belonging to the fortuitum group, present in drinking water. Oral treatment with M. manresensis for 2 weeks was able to induce a PPD-specific Tregs population, which has been related to a decrease in the neutrophilic infiltration found in TB lesions. Further mechanistic analysis using PPD-stimulated splenocytes links this 2-week treatment with heat-killed M. manresensis to IL-10 production and memory PPD-specific Tregs, and also to a weak PPD-specific global immune response stimulation, increasing IL-6, TNF, and IFN-γ production. In lungs, this treatment decreased the bacillary load, granulomatous infiltration and pro-inflammatory cytokines (TNF, IFN-γ, IL-6, and IL-17). Oral administration of M. manresensis during standard treatment for TB also significantly reduced the relapse of active TB after ending the treatment. Overall the data suggest that the use of heat-killed M. manresensis could be a new and promising tool for avoiding active TB induction and as adjunctive to TB treatment. This supports the usefulness of generating a new kind of protection based on a complex balanced immune response focused on both destroying the bacilli and including control of an excessive inflammatory response.
Highlights
Tuberculosis (TB) is a major global health problem, with 9 million new TB cases and 1.5 million deaths reported in 2013 (WHO, 2014)
A recent review of the pathology of human lesions based on necropsies from the pre-antibiotic era highlights the key role of neutrophils as inducers of exudative lesions, which are clearly responsible for the progression toward active TB (Cardona, 2015)
In order to study the mechanisms that modulate the inflammation in active TB, the Treg population was studied in C3HeB/FeJ mice and compared with the TB-resistant mouse strain C3H/HeN
Summary
Tuberculosis (TB) is a major global health problem, with 9 million new TB cases and 1.5 million deaths reported in 2013 (WHO, 2014). Understanding the infection’s progression to active TB is essential for finding new strategies to fight TB In this regard, induction of liquefaction in TB lesions has been identified as a key factor that allows extracellular growth of the bacilli and the development of cavities, thereby favoring spread of the infection (Grosset, 2003; Cardona, 2011). Induction of liquefaction in TB lesions has been identified as a key factor that allows extracellular growth of the bacilli and the development of cavities, thereby favoring spread of the infection (Grosset, 2003; Cardona, 2011) For this reason, we developed a murine model of active TB using a C3HeB/FeJ mice strain in which lesions liquefact, mimicking human-like progression (Marzo et al, 2014). We can conclude that the onset of active TB is a consequence of an excessive inflammatory response and the coalescence of different lesions (Vilaplana and Cardona, 2014)
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