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Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages.

ABSTRACT: Mycobacterium indicus pranii (MIP) known for its immunotherapeutic potential against leprosy and tuberculosis is undergoing various clinical trials and also simultaneously being studied in animal models to get insight into the mechanistic details contributing to its protective efficacy as a vaccine candidate. Studies have shown potential immunomodulatory properties of MIP, the most significant being the ability to induce strong Th1 type of response, enhanced expression of pro-inflammatory cytokines, activation of APCs and lymphocytes, elicitation of M.tb specific poly-functional T cells. All of these form crucial components of host-immune response during M.tb infection. Also, MIP was found to be potent inducer of autophagy in macrophages which resulted in enhanced clearance of M.tb from MIP and M.tb co-infected cells. Hence, we further examined the component/s of MIP responsible for autophagy induction. Interestingly, we found that MIP lipids and DNA were able to induce autophagy but not the protein fraction. LAM being one of the crucial components of mycobacterial cell-wall lipids and possessing the ability of immunomodulation; we isolated LAM from MIP and did a comparative study with M.tb-LAM. Stimulation with MIP-LAM resulted in significantly high secretion of pro-inflammatory cytokines and displayed high autophagy inducing potential in macrophages as compared to M.tb-LAM. Treatment with MIP-LAM enhanced the co-localization of M.tb within the phago-lysosomes and increased the clearance of M.tb from the infected macrophages. This study describes LAM to be a crucial component of MIP which has significant contribution to its immunotherapeutic efficacy against TB.

SUBMITTER: Singh B

PROVIDER: S-EPMC6812838 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages.

Singh Bindu B Saqib Mohd M Chakraborty Anush A Bhaskar Sangeeta S

PloS one 20191024 10

Mycobacterium indicus pranii (MIP) known for its immunotherapeutic potential against leprosy and tuberculosis is undergoing various clinical trials and also simultaneously being studied in animal models to get insight into the mechanistic details contributing to its protective efficacy as a vaccine candidate. Studies have shown potential immunomodulatory properties of MIP, the most significant being the ability to induce strong Th1 type of response, enhanced expression of pro-inflammatory cytoki ...[more]

PMID: 31648257

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Project description:BackgroundTuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis.MethodsUsing a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.ResultsThere was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer.ConclusionsIn patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Project description:BACKGROUND:Mycobacterium indicus pranii (MIP), popularly known as Mw, is a cultivable, non-pathogenic organism, which, based on its growth and metabolic properties, is classified in Runyon Group IV along with M. fortuitum, M. smegmatis and M. vaccae. The novelty of this bacterium was accredited to its immunological ability to undergo antigen driven blast transformation of leukocytes and delayed hypersensitivity skin test in leprosy patients, a disease endemic in the Indian sub-continent. Consequently, MIP has been extensively evaluated for its biochemical and immunological properties leading to its usage as an immunomodulator in leprosy and tuberculosis patients. However, owing to advances in sequencing and culture techniques, the citing of new strains with almost 100% similarity in the sequences of marker genes like 16S rRNA, has compromised the identity of MIP as a novel species. Hence, to define its precise taxonomic position, we have carried out polyphasic taxonomic studies on MIP that integrate its phenotypic, chemotaxonomic and molecular phylogenetic attributes. METHODOLOGY/PRINCIPAL FINDINGS:The comparative analysis of 16S rRNA sequence of MIP by using BLAST algorithm at NCBI (nr database) revealed a similarity of > or =99% with M. intracellulare, M. arosiense, M. chimaera, M. seoulense, M. avium subsp. hominissuis, M. avium subsp. paratuberculosis and M. bohemicum. Further analysis with other widely used markers like rpoB and hsp65 could resolve the phylogenetic relationship between MIP and other closely related mycobacteria apart from M. intracellulare and M. chimaera, which shares > or =99% similarity with corresponding MIP orthologues. Molecular phylogenetic analysis, based on the concatenation of candidate orthologues of 16S rRNA, hsp65 and rpoB, also substantiated its distinctiveness from all the related organisms used in the analysis excluding M. intracellulare and M. chimaera with which it exhibited a close proximity. This necessitated further analysis of MIP with more sensitive and segregating parameters to ascertain its precise taxonomic position as a new species. The analysis of MIP and its comparison with other mycobacterial reference strains based on cellular and biochemical features, growth characteristics and chemotaxonomic studies like FAME profiling confirmed that MIP is uniquely endowed with diverse metabolic attributes that effectively distinguishes it from all the closely related mycobacteria including M. intracellulare and M. chimaera. CONCLUSION:The results presented in this study coupled with the non-pathogenic nature and different biochemical and immunomodulatory properties of MIP affirm it as a distinct species belonging to M. avium complex (MAC). It is further proposed to use an earlier suggested name Mycobacterium indicus pranii for this newly established mycobacterial species. This study also exemplifies the growing need for a uniform, consensus based broader polyphasic frame work for the purpose of taxonomy and speciation, particularly in the genus Mycobacterium.

Project description:BackgroundIn the Investigation of the Management of Pericarditis (IMPI) randomized control, 2x2 factorial trial, Mycobacterium indicus pranii (MIP) immunotherapy, adjunctive corticosteroids or MIP combined with corticosteroids was compared to standard tuberculosis (TB) therapy for tuberculous pericarditis (TBP). While MIP and/or the combination of MIP and corticosteroids had no impact on all-cause mortality or pericarditis related outcomes, corticosteroids reduced the incidence of constrictive pericarditis at 12 months. Data suggests that both adjunctive therapies modulate the immune and inflammatory responses to pulmonary TB. Whether they affect systemic antigen-specific T cell responses, key immune mediators of Mycobacterium tuberculosis control, in patients with TBP is unknown.MethodsParticipants with definite or probable TBP were randomly assigned to receive five injections of MIP or placebo at 2-week intervals and either 6 weeks of oral prednisolone or placebo. Frequencies of CD4 and CD8 T cells expressing IFN-γ, IL-2 or TNF in response to MIP or purified protein derivative stimulation were measured by intracellular cytokine staining and flow cytometry up to 24 weeks post treatment.ResultsImmunotherapy with MIP did not significantly modulate frequencies of Th1 CD4 and CD8 T cells compared to placebo. Adjunctive prednisolone also did not change mycobacteria-specific CD4 or CD8 T cell responses. By contrast, combinatorial therapy with MIP and prednisolone was associated with a modest increase in frequencies of multifunctional and single cytokine-expressing CD4 T cell responses at 6 and 24 weeks post treatment.ConclusionsConsistent with the lack of a significant clinical effect in the IMPI trial, MIP immunotherapy did not significantly modulate mycobacteria-specific T cell responses. Despite the positive effect of prednisolone on hospitalizations and constrictive pericarditis in the IMPI trial, prednisolone did not significantly reduce pro-inflammatory T cell responses in this sub-study. The modest improvement of mycobacteria-specific T cell upon combinatorial therapy with MIP and prednisolone requires further investigation.

Dataset Information

Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages.

Publications

Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages.

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