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Visceral leishmaniasis (VL) is a disseminated and lethal disease of reticulo-endothelial system caused by protozoan parasites Leishmania donovani and L. infantum, which are known to induce host T cell suppression. To understand the impact of parasite load on T cell function, the present was focused on parasite load with T cell function in bone marrow of 26 VL patients. We observed significant enrichment of forkhead box protein 3 (FoxP3) (P = 0·0003) and interleukin (IL)-10 FoxP3 regulatory T cells (T ) (P = 0·004) in the bone marrow (BM) of patients with high parasite load (HPL) compared with low parasite load (LPL). Concordantly, T effector cells producing interferon (IFN)-γ (P = 0·005) and IL-17A (P = 0·002) were reduced in the BM of HPL. Blocking of T -cell derived suppressive cytokines [(IL-10 and transforming growth factor (TGF)-β] rescued the effector T cells and their functions. However, it was observed that TGF-β levels were dominant, favouring T cell differentiation. Furthermore, the low ratio of IL-6/TGF-β favours the suppressive milieu in HPL patients. Here we show the change in levels of various cytokines with the parasitic load during active VL, which could be helpful in devising newer immunotherapeutic strategies against this disease.

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth ( CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s). Keywords: polyfunctional T cells r PD-1 r Treg cells r tuberculosis r immunotherapyAdditional supporting information may be found online in the Supporting Information section at the end of the article. Abbreviations: MDM: monocyte-derived macrophage · M.tb: Mycobacterium tuberculosis · PFT: polyfunctional T cell · TB: tuberculosis

Mycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The DNA binding and DNA methyltransferase activity of Rv1515c was confirmed in vitro. Knock-in of Rv1515c in a model mycobacteria M. smegmatis (M. s_Rv1515c) resulted in remarkable physiological and morphological changes and conferred the recombinant strain with an ability to adapt to various stress conditions, including resistance to TB drugs. M. s_Rv1515c was phagocytosed at a greater rate and displayed extended intra-macrophage survival in vitro. Recombinant M. s_Rv1515c contributed to enhanced virulence by suppressing the host defense mechanisms including RNS and ROS production, and apoptotic clearance. M. s_Rv1515c, while suppressing the phagolysosomal maturation, modulated pro-inflammatory cytokine production and also inhibited antigen presentation by downregulating the expression of MHC-I/MHC-II and co-stimulatory signals CD80 and CD86. Mice infected with M. s_Rv1515c produced more Treg cells than vector control (M. s_Vc) and exhibited reduced effector T cell responses, along-with reduced expression of macrophage activation markers in the chronic phase of infection. M. s_Rv1515c was able to survive in the major organs of mice up to 7 weeks post-infection. These results indicate a crucial role of Rv1515c in M. tb pathogenesis.

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Background Cell-mediated immunity plays an important role in host defence against fungal pathogens, regulated by differentiation of lymphocytes towards T-helper 1 or 2 cells. This study reports intracellular cytokine variation in terms of invasive fungal sinusitis type and outcome. Methods The mononuclear leukocytes of 15 patients with invasive fungal sinusitis (mucormycosis in 8, aspergillus in 7) were stained with antibodies against intracellular cytokines, after fungal antigen stimulation and culture, and immunophenotyped. Patients were followed up for six months, with clinical course categorised as improvement, worsening or death. Results The mean percentages of mononuclear cells producing interleukins 4, 5, 10 and 12, and interferon-γ, in the mucormycosis group were 0.575, 0.284, 8.661, 4.460 and 1.134, respectively, while percentages in the aspergillosis group were 0.233, 0.492, 4.196, 4.466 and 1.533. Cells producing interleukin 4 and 10 were higher in the mucormycosis group, while those producing interleukin-12 and interferon-γ were lower. Cells producing interleukins 4 and 12 were higher in patients with a poor outcome (p-values of 0.0662 and 0.0373, respectively), while those producing interferon-γ were lower (p = 0.0864). Conclusion Adaptive cell-mediated immunity is expressed differently in two categories of invasive fungal sinusitis, and the cytokine expression pattern is related to prognosis.