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The microbiota of the gut-lung axis affects local and far-reaching immune responses and might also trigger chronic and inflammatory diseases. We hypothesized that gut dysbiosis induced by obesity, which coexists in countries with a high tuberculosis burden, aggravates the host susceptibility and the pulmonary damage tolerance. To assess our hypothesis, we used a model of high-fat diet (HFD)-induced obesity, followed by infection of C57BL/6 mice with Mycobacterium tuberculosis . We showed that obesity increased the susceptibility, the pulmonary inflammation and IFN-γ levels in M. tuberculosis -infected mice. During the comorbidity obesity and tuberculosis, there is an increase of Bacteroidetes and Firmicutes in the lungs, and an increase of Firmicutes and butyrate in the feces. Depletion of gut microbiota by antibiotic treatment in the obese infected mice reduced the frequencies of CD4 + IFN-γ + IL-17 - cells and IFN-γ levels in the lungs, associated with an increase of Lactobacillus . Our findings reinforce the role of the gut-lung axis in chronic infections and suggest that the gut microbiota modulation may be a potential host-directed therapy as an adjuvant to treat TB in the context of IFN-γ-mediated immunopathology.

Background: The lung lesions in an individual infected with tuberculosis (TB) are surprisingly variable and independent of each other. However, there is no circulating biomarker yet able to segregate patients according to the extent of lung lesions., Materials and Methods: In this study, the phenotypic and functional profile of leukocytes of patients with active pulmonary tuberculosis (TB) and controls (CO) were fully scrutinized by immunophenotyping assays and in vitro short-term whole blood culture. The TB group was subdivided according to the extent of lung lesions as unilateral (UNI) and bilateral (BI)., Results: The results show that TB group display an altered leukocyte profile in the peripheral blood with significant lower counts of NK-cells, CD3 + CD56 + CD16 +/- NKT-cells, CD4 + T-cells, CD19 + B-cells when compared to CO. Increased CD4 + T-cells and CD8 + T-cell activation was observed by the upregulation of activation markers (HLA-DR) as well as of chemokine receptors (CCR2, CCR3, and CXCR4). In addition, TB group presented a significant decrease proportion of CD14 Low CD16 + monocytes despite the increase in HLA-DR expression. Regarding the severity of the disease, in the BI group a reduction in frequency of CD19 + CD5 + B-cells and expression of HLA-DR in CD14 Low CD16 + monocytes was observed. Furthermore, the extent of lung lesions influences the production of molecules as observed by significantly larger production of IL-4 by neutrophils, total T-cells, CD4 + T-cells, CD8 + T-cells and CD19 + B-cells in UNI as compared to BI. By contrast, in BI group the frequency of high producers of both IL-17 + CD4 + T-cells and IL-17 + CD8 + T-cells were significantly increased than UNI, suggesting the deleterious role of these subsets during active pulmonary Mtb infection., Conclusion: The immunophenotypic characterization of unilateral and bilateral active TB performed in the present study indicates that the extent of lung lesion could be associated with a fine-tuning between immunological responses during untreated Mtb infection., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Previously we showed that 65-kDa Mycobacterium leprae heat shock protein (Hsp65) is a target for the development of a tuberculosis vaccine. Here we evaluated peripheral blood mononuclear cells (PBMC) from healthy individuals or tuberculosis patients stimulated with two forms of Hsp65 antigen, recombinant DNA that encodes Hsp65 (DNA-HSP65) or recombinant Hsp65 protein (rHsp65) in attempting to mimic a prophylactic or therapeutic study in vitro, respectively. Proliferation and cytokine-producing CD4 + or CD8 + cell were assessed by flow cytometry. The CD4 + cell proliferation from healthy individuals was stimulated by DNA-HSP65 and rHsp65, while CD8 + cell proliferation from healthy individuals or tuberculosis patients was stimulated by rHSP65. DNA-HSP65 did not improve the frequency of IFN-gamma + cells from healthy individuals or tuberculosis patients. Furthermore, we found an increase in the frequency of IL-10-producing cells in both groups. These findings show that Hsp65 antigen activates human lymphocytes and plays an immune regulatory role that should be addressed as an additional antigen for the development of antigen-combined therapies.