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

The aerial parts extract of Momordica charantia plant were used for the corrosion resistance of carbon steel in the acidic medium (0.5 M H2SO4) utilizing weight loss method, Tafel and Electrochemical Impedance Spectroscopy. The state of mixed inhibitor adsorption on the carbon steel surface is shown by potentiodynamic polarization. M. charantia achieved the extraordinary inhibition efficiency of 93.51% at 500 mg/L of inhibitor concentration. Scanning electron microscopy and atomic force microscopy were used to know about the thin layer which was formed on the surface of carbon steel for its protection from corrosion and the adsorption of inhibitor was shown by UV–vis. spectroscopic technique. Fourier Transform Infrared Spectroscopy technique confirmed the existence of functional groups and the heteroatoms exhibit in the inhibitor. Adsorbance by the inhibitory molecules on the carbon steel surface followed the Langmuir adsorption isotherm. Hypothetical investigations (computational) showed a very valuable report. All acquired outcomes ensure that M. charantia extract can procedure an effectual preventing layer and restrict the corrosion procedure.

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Host T cell response plays a critical role in containment of M. tuberculosis (Mtb) infection by granuloma formation. The prevalence of multidrug-resistance tuberculosis (MDR-TB) among immunocompromised hosts (HIV co-infection & posttransplant patients) indicate the influence of host T cell response on MDR TB. Previously, we have shown critical role of regulatory T (Treg) cells and PD-1 pathway causing suppressed state of T cell response against Mycobacterium tuberculosis (Mtb) among TB patient.In this study, we attempted to understand the status of host immune response among the MDR and Drug Sensitive (DS) TB patients. We also checked the contribution of PD-1 pathway on poly-functional T cells (PFTs), critical for protective immunity in TB. METHODS:For immune response profile and in vitro experiments, polychromatic flowcytometry based immunological assays were performed. PD1 blocking experiments were performed in mice infected with Mtb and invitro model where monocyte derived macrophages (MDM) were infected with virulent Mtb DS strains. Furthermore, the impact of cytokine on the efflux pump of bacteria was evaluated using virulent Mtb DS strains infected MDM in presence of pro and anti-inflammatory cytokines. RESULTS:We observed marked reduction of polyfunctional T cells (PFTs) in TB patients. PFTs could be significantly rescued by blocking PD-1 pathway, which resulted in effective clearance of Mtb in MDM in vitro model. Blocking PD-1 pathway in mice infected with Mtb, demonstrated decrease in Tregs and restoration of PFTs with enhanced reduction of bacillary load in the lung & spleen relative to chemotherapy alone. Among MDR patients, we observed increase in the frequency of Tregs and decrease in frequency of Mtb specific T cell cytokine producers (IFN-g or TNF-a or IFN-gþ TNF-aþ) compared to DS TB patients, suggesting a tight correlation of Treg mediated suppression with MDR status. Furthermore, we observed higher expression of efflux pump in DR strains which could be substantially modulated by pro-inflammatory (IFN-g, TNF-a) and anti-inflammatory cytokines (IL10 and TGF b) in in vitro MDM model. Suppressive cytokines (IL10 and TGF b) increased the efflux pump of Mtb. This is suggestive of possible causal relation of host immune status with the drug efflux pump expression in Mtb. CONCLUSIONS:Our results demonstrate elicitation of weaker effector T cell response in DR TB compared to DS TB patients. Additionally, our findings suggest critical role of PD-1 in suppressing the protective immune response in TB. Rescuing PFTs by blocking PD-1 pathway may offer a novel strategy for adjunct immunotherapy in TB. This may be more relevant in MDR TB as PFT response may modulate the drug pump so as to increase the efficacy of chemotherapy.CLINICAL IMPLICATIONS: Rescuing appropriate immune response may improve the efficacy of anti-tubercular therapy in TB, especially for MDR TB with possible reduction of duration of drug therapy and relapse.

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