Indicus Pranii Research Articles

Synergistic role of Mycobacterium indicus pranii and human beta Defensin-2 as adjunctive therapy against Mycobacterium tuberculosis

Host-directed therapies (HDT) via modulation of specific host responses like inflammation can limit mycobacterial infection. HDTs could be included in current TB therapy as an adjunct to increase bacterial clearance and limit tissue damage to control spread. Individually, Mycobacterium indicus pranii (MIP) and human beta defensin-2 (hBD-2) are promising therapies for tuberculosis (TB). They can directly target the TB bacilli and enhance cell-mediated immune responses, which is limiting with conventional drugs. Therefore, our study investigated the combined application of MIP and hBD-2 to evaluate their efficacy in clearing infections caused by Mycobacterium smegmatis (M.smeg) and Mycobacterium tuberculosis (M.tb) (both avirulent; H37Ra and virulent strain; H37Rv) in THP-1 cells and human monocyte-derived macrophages (MDMs). A strong pro-inflammatory response was observed against the combination of MIP and hBD-2 which also correlated with a significant reduction in the bacterial load. This combination further showed protection against M.tb by enhancing pyroptosis in the infected cells. The study suggests the combined use of these potent immunomodulators, which could be employed as an effective mode of therapy as adjuvants against mycobacterial infections after validation in a suitable animal model.

Therapeutic potential of Zanha africana (Radlk.) Exell: antimycobacterial activity and safety evaluation

BackgroundZanha africana (Radlk.) Exell extracts are commonly utilized in Tanzania and other countries for treating conditions associated with HIV and AIDS, including tuberculosis (TB). In Tanzania, it is listed among the most frequently traded plant species for medicinal use in different marketplaces. However, limited literature exists regarding its antimycobacterial properties and safety profile. ObjectiveThis study aimed to evaluate Z. africana ethanolic extract for safety and antimycobacterial activity. MethodsThe antimycobacterial activity of the crude extracts was assessed using the broth microdilution method against various non-pathogenic mycobacteria strains including Mycobacterium aurum (MA), Mycobacterium madagascariense (MM), and Mycobacterium indicus pranii (MIP). Bioassay-guided fractionation was employed to isolate the active compounds. The safety profile of the crude extract was investigated through cytotoxicity assay on peripheral blood mononuclear cells (PBMCs) and the brine shrimp lethality test. ResultsThe 80% ethanolic extracts of Z. africana demonstrated activity against all tested non-pathogenic mycobacteria. The antimycobacterial activity of ethanolic extract of the stem bark was 625 µg/mL, 313 µg/mL and 125 µg/mL against MA, MM, and MIP, respectively. The most potent fraction was the ethyl acetate fraction, from which two active compounds were isolated: proanthocyanidin A2; Compound (1) and its monomer epicatechin, Compound (2). Compound (1) exhibited higher antimycobacterial activity compared to compound (2) with minimum inhibitory concentrations (MICs) of 19.50 µg/mL and 12.98 µg/mL against MM and MIP respectively. The ethanolic extract did not demonstrate toxicity on PBMCs and brine shrimps. ConclusionThis study demonstrates that Z. africana extracts and the isolated compounds possess antimycobacterial activity. This provides evidence supporting the traditional use of Z. africana extracts for TB management. Further research is recommended to comprehensively evaluate the efficacy and safety of the plant constituents using different models.

PreVenTB trial: protocol for evaluation of efficacy and safety of two vaccines VPM1002 and Immuvac (Mw) in preventing tuberculosis (TB) in healthy household contacts of newly diagnosed sputum smear-positive pulmonary TB patients: phase III, randomised, double-blind, three-arm placebo-controlled trial

IntroductionTuberculosis (TB) continues to be one of the deadliest infectious diseases over the centuries, killing more people worldwide than any other single infectious disease. There is an urgent need for...

Genome wide screening to discover novel toxin-antitoxin modules in Mycobacterium indicus pranii; perspective on gene acquisition during mycobacterial evolution.

Mycobacterium indicus pranii (MIP), a benign saprophyte with potent immunomodulatory attributes, holds a pivotal position in mycobacterial evolution, potentially serving as the precursor to the pathogenic Mycobacterium avium complex (MAC). Despite its established immunotherapeutic efficacy against leprosy and notable outcomes in gram-negative sepsis and COVID-19 cases, the genomic and biochemical features of MIP remain largely elusive. This study explores the uncharted territory of toxin-antitoxin (TA) systems within MIP, hypothesizing their role in mycobacterial pathogenicity regulation. Genome-wide screening, employing diverse databases, unveils putative TA modules in MIP, setting the stage for a comparative analysis with known modules in Mycobacterium tuberculosis, Mycobacterium smegmatis, Escherichia coli, and Vibrio cholerae. The study further delves into the TA network of MAC and Mycobacterium intracellulare, unraveling interactive properties and family characteristics of identified TA modules in MIP. This comprehensive exploration seeks to illuminate the contribution of TA modules in regulating virulence, habitat diversification, and the evolutionary pathogenicity of mycobacteria. The insights garnered from this investigation not only enhance our understanding of MIP's potential as a vaccine candidate but also hold promise in optimizing tuberculosis drug regimens for expedited recovery.

The Role of Mycobacterium indicus pranii in Sepsis Management: A Comprehensive Review of Clinical Outcomes and Therapeutic Potential.

Sepsis is a critical condition characterized by a dysregulated immune response to infection, leading to systemic inflammation, multi-organ failure, and high mortality rates. Current treatments primarily involve antibiotics and supportive care, which address the infection and stabilize hemodynamics but do not directly modulate the inflammatory response. This limitation highlights the need for novel therapeutic approaches. This review aims to evaluate the role of Mycobacterium indicus pranii (MIP) in sepsis management, focusing on its clinical outcomes and therapeutic potential. By examining preclinical and clinical evidence, we seek to understand the efficacy, safety, and practical applications of MIP in treating sepsis. A comprehensive review of existing literature was conducted, including preclinical studies, clinical trials, and case reports involving MIP. The review synthesizes findings related to its mechanism of action, therapeutic efficacy, and safety profile. MIP has demonstrated significant immunomodulatory effects, including enhancing innate and adaptive immune responses and reducing excessive inflammation. Clinical trials have shown promising results, with MIP improving clinical outcomes and reducing sepsis-related complications. The agent's unique ability to modulate the cytokine storm associated with sepsis positions it as a potential adjunctive therapy. MIP offers a novel approach to managing sepsis by addressing immune dysregulation and inflammation. The evidence suggests that MIP could be a valuable adjunct to current treatments, improving patient outcomes and addressing some limitations of conventional therapies. Further research is needed to establish its role in clinical practice and to optimize treatment protocols.

MIP vaccine in leprosy: A scoping review and future horizons.

Mycobacterium Indicus Pranii (MIP) vaccine is a killed vaccine developed in India for leprosy with immunotherapeutic as well as immunoprophylactic effects. MIP, earlier known as Mycobacterium welchii, is a rapidly growing non-pathogenic mycobacterium. The novelty of this bacterium is due to its translational application as an immunotherapeutic agent. When administered intradermally, the vaccine induces cell-mediated immunity in the host towards Mycobacterium leprae. It leads to faster clinical and histopathological improvement, rapid bacillary clearance, and also lepromin conversion in anergic leprosy patients. The beneficial role of the MIP vaccine in augmenting the therapeutic efficacy of Multidrug Therapy (MDT), particularly in highly bacillated leprosy patients, is well documented in various studies from India. The role of the vaccine in reactional states is controversial, with varied results in different studies. Overall, it is found to decrease the frequency of type 2 lepra reactions and is useful in recalcitrant erythema nodosum leprosum. Even though there may be an increased likelihood of type 1 reactions, no additional nerve function impairment is attributed to the vaccine in various studies. In household contacts of leprosy who are administered MIP, it is noted to confer protection from disease lasting up to 10 years. It may prove to be a cost-effective strategy in national leprosy programmes. Apart from local injection site reactions, the vaccine is relatively safe, but it is not recommended in pregnancy and lactation. This article provides an overview of the MIP vaccine's clinical application in the context of leprosy spanning over 40 years. It also considers the vaccine's possible future applications in the management of disease-related complications and achieving the long-term goal of zero leprosy.

Assessing the hazard of death, cardiac tamponade, and pericardial constriction among HIV and tuberculosis pericarditis patients using the extended Cox-hazard model: Intervention study.

Tuberculous (TB) pericarditis (TBP), a TB of the heart, is linked to significant morbidity and mortality rates. Administering glucocorticoid therapy to individuals with TBP might enhance overall results and lower the likelihood of fatality. However, the actual clinical effectiveness of supplementary glucocorticoids remains uncertain. This study specifically evaluated the effects of prednisolone, prednisolone-antiretroviral therapy (ART) interaction, and other potential risk factors in reducing the hazard of the composite outcome, death, cardiac tamponade, and constriction, among TBP and human immunodeficiency virus (HIV) patients. The data used in this study were obtained from the investigationof the Management of Pericarditis trial, a multicentre international randomized double-blind placebo-controlled factorial study that investigated the effects of two TB treatments, prednisolone and Mycobacterium indicus pranii immunotherapy in patients with TBPin Africa. This study used a sample size of 587 TBP and HIV-positivepatients randomized into prednisolone and its corresponding placebo arm. We used the extended Cox-proportional hazard model to evaluate the effects of the covariates on the hazard of the survival outcomes. Models fitting and parameter estimation were carried out using R version 4.3.1. Prednisolone reduces the hazard of composite outcome (hazrad ratio [HR] = 0.32, 95% confidence interval [CI] = , p < 0.001), cardiac tamponade (HR = 0.14, 95%CI = 0.05, 0.42, p < 0.001) and constriction (HR = 0.81, 95%CI = 0.41, 1.61, p = 0.55). However, prednisolone increases the hazard of death (HR = 1.58, 95%CI = 1.11, 2.24, p = 0.01). Consistent usage of ART reduces the hazard of composite outcome, death, and constriction but insignificantly increased the hazard of cardiac tamponade. The study offers valuable insights into how prednisolone impact the hazard of different outcomes in patients with TBP and HIV. The findings hold potential clinical significance, particularly in guiding treatment decisions and devising strategies to enhance outcomes in this specific patient group. However, there are concerns about prednisolone potentially increasing the risk of death due to HIV-related death.

Activation of neutrophils excels the therapeutic potential of Mycobacterium indicus pranii and heat-induced promastigotes against antimony-resistant Leishmania donovani infection.

Repurposing drugs and adjuvants is an attractive choice of present therapy that reduces the substantial costs, chances of failure, and systemic toxicity. Mycobacterium indicus pranii was originally developed as a leprosy vaccine but later has been found effective against Leishmania donovani infection. To extend our earlier study, here we reported the immunotherapeutic modulation of the splenic and circulatory neutrophils in favour of hosts as neutrophils actually serve as the pro-parasitic portable shelter to extend the Leishmania infection specifically during the early entry into the hosts' circulation. We targeted to disrupt this early pro-parasitic incidence by the therapeutic combination of M. indicus pranii and heat-induced promastigotes against antimony-resistant L. donovani infection. The combination therapy induced the functional expansion of CD11b+Ly6CintLy6Ghi neutrophils both in the post-infected spleen, and also in the circulation of post-treated animals followed by the immediate Leishmania infection. More importantly, the enhanced expression of MHC-II, phagocytic uptake of the parasites by the circulatory neutrophils as well as the oxidative burst were induced that limited the chances of the very early establishment of the infection. The enhanced expression of pro-inflammatory cytokines, like IL-1α and TNF-α indicated resistance to the parasite-mediated takeover of the neutrophils, as these cytokines are critical for the activation of T cell-mediated immunity and host-protective responses. Additionally, the induction of essential transcription factors and cytokines for early granulocytic lineage commitment suggests that the strategy not only contributed to the peripheral activation of the neutrophils but also promoted granulopoiesis in the bone marrow.

Granulomatous dermatitis post Mycobacterium Indicus Pranii (MIP) vaccine in severe covid-19 infection: an exaggerated hypersensitivity phenomenon

Granulomatous dermatitis post Mycobacterium Indicus Pranii (MIP) vaccine in severe covid-19 infection: an exaggerated hypersensitivity phenomenon

Role of Mycobacterium indicus pranii in clinical outcomes in patients with sepsis: A systematic review and meta-analysis of randomised controlled trials.

Sepsis-induced immunosuppression appears to be reversible with immunomodulatory drugs. Mycobacterium indicus pranii (MIP) stimulates the Th1 type of immune response. This systematic review and meta-analysis of randomised controlled trials (RCTs) was aimed to find out if MIP is effective at improving clinical outcomes in sepsis patients. The databases (PubMed, Google Scholar, Web of Science, and Cochrane Library), along with preprint servers until June 2023, were searched. The methodology was evaluated using the 'Cochrane Collaboration risk of bias-2 tool' for RCT. The study included patients more than 18 years of age with sepsis within 48 h of first organ dysfunction. The primary outcome was 28-day mortality, and secondary outcomes were the length of stay in the intensive care unit (ICU), days on vasopressor support, ventilator-associated pneumonia (VAP), secondary infections, catheter-related bloodstream infections (CRBSI), and the delta sequential organ failure assessment (SOFA) score. The meta-analysis included two studies with 252 participants. In a pooled analysis, mortality in the MIP group was 43% lower than in the control (RR: 0.57, 95%CI: 0.33-1); however, this difference was statistically not significant. We observed the days on a vasopressor day (standardised mean difference [SMD]: 0.38; 95%CI: -1.20 to 0.44), length of ICU stay (SMD: 0.46; 95%CI: -1.44 to 0.51), secondary infection (RR: 0.75; 95%CI: 0.19-3.01), VAP (RR: 0.6; 95%CI: 0.28-1.56), CRBSI (RR: 0.97, 95%CI: 0.14-6.98), delta SOFA score (SMD: 0.88, 95%CI: -1.66 to - 0.10) between the two groups. Our findings observed preliminary evidence in the trends for a positive association of MIP with better outcomes in sepsis patients.

Antimycobacterial activity of scopoletin from ethanolic extract of Hymenodictyon floribundum (Hochst. & Steud.) B.L.Rob. Stem bark

The available tuberculosis (TB) therapies are taken for long time with complex regimens associated with adverse effects and drug-drug interactions. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis and HIV co-infections necessitates the need for continued search for new effective anti-TB alternative leads with different mechanisms of action and safety profile. The aim of this study was to isolate and characterize antimycobacterial compounds from Hymenodictyon floribundum (Hochst. & Steud.) B.L.Rob. a plant used traditionally in the management of HIV/AIDS-related conditions. Antimycobacterial activity of the plant extracts and its constituents against Mycobacterium indicus pranii (MIP) and Mycobacterium madagascariense (MM) was tested using a twofold broth micro-dilution technique. Bioassay-guided isolation was used to isolate active compounds. Isolated compounds were also tested for activity against clinical isolates of Mycobacterium tuberculosis (Mtb). The crude plant extract had antimycobacterial activity and its ethyl acetate fraction was the most active with minimum inhibitory concentration (MIC) values of 97 µg/ml and 197 µg/ml against MIP and MM respectively. Three compounds were isolated from the ethyl acetate fraction; 7‑hydroxy-6-methoxycoumarin (1), 7,7′-dihydroxy-6,6′-dimethoxy-3,3′-biscoumarin (2) and 7,7′-dihydroxy-6,6′-dimethoxy-8,8′-biscoumarin (3). Compound 1 had growth inhibitory activity against MIP, MM and Mtb with MIC values of 0.2 M against MIP, 0.41 M against MM, 0.78 M against Mtb1 and 1.63 M against Mtb2. In conclusion, 7-Hydroxy-6- methoxycoumarin exhibited moderate antimycobaterial activity. The findings from this study support the use of H. floribundum by traditional health practitioners for treatment of HIV and AIDS-related conditions.

Type 1 interferon mediated signaling is indispensable for eliciting anti-tumor responses by Mycobacterium indicus pranii.

The evolving tumor secretes various immunosuppressive factors that reprogram the tumor microenvironment (TME) to become immunologically cold. Consequently, various immunosuppressive cells like Tregs are recruited into the TME which in turn subverts the anti-tumor response of dendritic cells and T cells.Tumor immunotherapy is a popular means to rejuvenate the immunologically cold TME into hot. Mycobacterium indicus pranii (MIP) has shown strong immunomodulatory activity in different animal and human tumor models and has been approved for treatment of lung cancer (NSCLC) patients as an adjunct therapy. Previously, MIP has shown TLR2/9 mediated activation of antigen presenting cells/Th1 cells and their enhanced infiltration in mouse melanoma but the underlying mechanism by which it is modulating these immune cells is not yet known. This study reports for the first time that MIP immunotherapy involves type 1 interferon (IFN) signaling as one of the major signaling pathways to mediate the antitumor responses. Further, it was observed that MIP therapy significantly influenced frequency and activation of different subsets of T cells like regulatory T cells (Tregs) and CD8+ T cells in the TME. It reduces the migration of Tregs into the TME by suppressing the expression of CCL22, a Treg recruiting chemokine on DCs and this process is dependent on type 1 IFN. Simultaneously, in a type 1 IFN dependent pathway, it enhances the activation and effector function of the immunosuppressive tumor resident DCs which in turn effectively induce the proliferation and effector function of the CD8+ T cells. This study also provides evidence that MIP induced pro-inflammatory responses including induction of effector function of conventional dendritic cells and CD8+ T cells along with reduction of intratumoral Treg frequency are essentially mediated in a type 1 IFN-dependent pathway.

Abstract 554: The role of Mycobacterium w as a novel treatment for osteosarcoma

Abstract Osteosarcoma (OS) is the most common malignant primary tumor of bone and occurs in adolescents and young adults as well as in the elderly. Despite a number of large clinical trial efforts, metastatic sarcoma remains a lethal disease, and there have been no meaningful advances in therapy or improvements in patient outcomes for decades. Mycobacterium w (Mw, also known as Mycobacterium indicus pranii) is a non-pathogenic strain of mycobacterium which has been used as an immunomodulator against leprosy, tuberculosis and several cancers and is approved for treatment of NSCLC along with chemotherapy in India. Mw promotes a Th1 immune response and its administration in tumor bearing animals is associated with an increase in total number of tumor infiltrating immune cells (TIIC) with decrease in FOXP3 and PD-1 expressing TIIC in pancreatic cancer and melanoma. Previous studies in our lab have shown that Mw promotes mature dendritic cell and activated CD8+ T cell accumulation within the tumor microenvironment in a mouse model of pancreatic cancer. We compared the effects Mw with standard of care doxorubicin on OS tumor progression in a subcutaneous K7M2 syngeneic mouse model. Mw treatment was more effective at tumor inhibition than doxorubicin. Immunohistochemistry analyses of OS tumors revealed an increase in macrophages following Mw treatment. We aim to further analyze the tumor immune microenvironment using a panel of 28 antibodies to determine alterations due to Mw treatment. With these results we hope to show that Mw is a promising candidate for further development as a therapy for OS. Citation Format: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Sushil Kumar, Wenqi Li, Rajiv Modi, Manjul Joshipura, Bakulesh Khamar, Lara E. Davis, Sanjay V. Malhotra. The role of Mycobacterium w as a novel treatment for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 554.

A prospective randomized controlled study of Mycobacterium Indicus Pranii vaccine, Measles Mumps Rubella vaccine and Vitamin D3 in extragenital cutaneous warts.

Interventional, prospective, four arm randomized control. Outpatient department, Department of Dermatology, Venereology and Leprology, AIIMS Jodhpur (Rajasthan), India. Two hundred patients. The intervention administered in the groups were normal saline (A), vitamin D3 (B), MIP (C), and MMR (D). The injections were given into the largest wart at 2-weekly intervals until complete clearance or for a maximum of seven sittings. Post-treatment clearance of the injected wart and the distant wart was compared on the basis of change in wart number, percentage clearance, and mean time to complete clearance. Side effects were recorded. A total of 197 patients were recruited. The mean percentage improvement in the injected and non-injected warts was 68.4% and 66.8%, respectively. Intention to treat analysis (ITT) showed that complete clearance of lesions in injected wart occurred in placebo, vit D3 , MMR, and MIP arms in 64%, 66%, 58%, and 55% patients, respectively (p > 0.05), while in the non-injected warts in 62%, 64%, 52%, and 53%, respectively (p > 0.05). The mean time to achieve complete clearance of wart was fastest in MIP at 7.1 weeks followed by MMR at 7.2 weeks, VIT D3 at 7.4 weeks and in placebo group 7.8 weeks (p > 0.05). Side effects noted were fever, pain, erythema, and swelling which was highest in VIT D3 group (p < 0.05). The efficacy of immunotherapies was comparable to placebo with minimal side effects.

Mycobacterium indicus pranii therapy suppresses systemic dissemination of tumor cells in B16F10 murine model of melanoma

Cancer associated morbidity is mostly attributed to the dissemination of tumor cells from their primary niche into the circulation known as “metastasis”. Mycobacterium indicus pranii (MIP) an approved immunotherapeutic agent against lung cancer (NSCLC) has shown potent anti-tumor activity in prior studies. While evaluating anti-tumor activity of MIP in mouse model, MIP treated animals typically exhibited less metastatic lesions in their pulmonary compartment. To study the role of MIP in metastasis closely, B16F10 melanoma cells were implanted subcutaneously in the mice, and the dissemination of tumor cells from the solid tumor was evaluated over a period of time. When B16F10 melanoma cells were treated with MIP in vitro, downregulation of epithelial mesenchymal transition markers was observed in these cells, which in turn suppressed the invasion, migration and adhesion of tumor cells. Notably, MIP therapy was found to be effectively reducing the metastatic burden in murine model of melanoma. Molecular characterization of MIP treated tumor cells substantiated that MIP upregulates the PPARγ expression within the tumor cells, which attenuates the NFκB/p65 levels within the nucleus, resulting in the suppression of Mmp9 expression in tumor cells. Besides that, MIP also downregulated the surface expression of chemokine receptor CXCR4 in murine melanoma cells, where chromatin immunoprecipitation confirmed the impeded recruitment of p50 and c-Rel factors to the Cxcr4 promoter, resulting in its downregulation transcriptionally. Taken together, MIP suppressed the dissemination of tumor cells in vivo, by regulating the expression of MMP9 and CXCR4 on these cells.

Bioassay-guided isolation of antimycobacterial compounds from Aphloia theiformis (Vahl) Benn root ethanolic extract

BackgroundAphloia theiformis is used in Makete district, Tanzania, and other areas by HIV and AIDS patients as a weight loss remedy and for treatment of tuberculosis. However, there is no literature information on its antimycobacterial activity. PurposeTo evaluate antimycobacterial activity of A. theiformis root ethanolic extract and isolated compounds. MethodsThe broth microdilution method was used to test the crude root ethanolic extract for activity against different non-pathogenic mycobacteria. Bioautography was used to identify the active constituents. Isolation of the active compounds was carried out using bioassay-guided fractionation. Chemical structures of compounds were established by comparison of their spectra with literature spectral data. The isolated compounds and some fractions were screened for activity against M. tuberculosis (MTB) subtype H37Rv and clinical isolates of MTB including strains resistant to rifampicin. ResultsThe 80% ethanolic extract of A. theiformis displayed activity against all non-pathogenic mycobacteria. The most active fraction was the ethyl acetate fraction from which two compounds were isolated; an epicatechin dimer; proanthocyanidin A2 (1) and tormentic acid (2) belonging to ursane pentacyclic triterpenoid. Compound (1) had MICs of 60.7 µM against Mycobacterium madagascariense and Mycobacterium indicus pranii and 255 µM against both standard MTB (H37Rv) and clinical isolate of rifampicin-resistant MTB. ConclusionThis study provides evidence in support of the use of A. theiformis extracts by traditional health practitioners for the management of tuberculosis. We recommend more studies to further assess efficacy and safety of the plant constituents using different models.

Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.

Targeting immunotherapeutics inside the tumor microenvironment (TME) with intact biological activity remains a pressing issue. Mycobacterium indicus pranii (MIP), an approved adjuvant therapy for leprosy has exhibited promising results in clinical trials of lung (NSCLC) and bladder cancer. Whole MIP as well as its cell wall fraction have shown tumor growth suppression and enhanced survival in mice model of melanoma, when administered peritumorally. Clinically, peritumoral delivery remains a procedural limitation. In this study, a tumor targeted delivery system was designed, where chitosan nanoparticles loaded with MIP adjuvants, when administered intravenously showed preferential accumulation within the TME, exploiting the principle of enhanced permeability and retention effect. Bio-distribution studies revealed their highest concentration inside the tumor after 6h of administration. Interestingly, MIP adjuvant nano-formulations significantly reduced the tumor volume in the treated groups and increased the frequency of activated immune cells inside the TME. For chemoimmunotherapeutics studies, MIP nano-formulation was combined with standard dosage regimen of Paclitaxel. Combined therapy exhibited a further reduction in tumor volume relative to either of the MIP nano formulations. From this study a three-pronged strategy emerged as the underlying mechanism; chitosan and Paclitaxel have shown direct role in tumor cell death and the MIP nano-formulation activates the tumor residing immune cells which ultimately leads to the reduced tumor growth.

Mycobacterium Indicus Pranii (MIP) Vaccine: Pharmacology, Indication, Dosing Schedules, Administration, and Side Effects in Clinical Practice

Mycobacterium indicus pranii (MIP), previously called Mw vaccine, is a one-of-a-kind immunomodulatory vaccine. It was indigenously developed in India for use in leprosy. MIP is heat-killed Mycobacterium w, which is a non-pathogenic atypical mycobacterium belonging to Class IV of Runyon classification. It shares epitopes with Mycobacterium leprae and Mycobacterium tuberculosis, which forms the rationale behind its use in leprosy and tuberculosis. MIP activates both innate and acquired immunity. It induces a Th1 and Th17 immune response along with downregulation of Th2 pathway and activates macrophages and dendritic cells. MIP vaccine is safe with adverse effects such as local site erythema, swelling, and rarely fever and other systemic reactions. Apart from leprosy, MIP has been used in dermatological diseases such as warts and psoriasis. Clinical trials have evaluated the efficacy of MIP in a plenitude of non-dermatological conditions such as category II tuberculosis, Gram-negative sepsis, non-small cell lung cancer, human immunodeficiency virus (HIV), muscle-invasive bladder cancer, and very recently, coronavirus 2019 (COVID-19). In vitro and animal studies have also demonstrated its utility in leishmaniasis, melanoma, and as a vaccine for the prevention of pregnancy. The PubMed database was searched using “Mycobacterium indicus pranii, MIP, Mycobacterium w” as the keyword in title. This comprehensive review provides useful information for healthcare professionals about immunotherapeutic potential of MIP vaccine, its composition, dosing schedule, administration, and side effects besides its efficacy in various indications other than leprosy.

High diversity of clinical Mycobacterium intracellulare in China revealed by whole genome sequencing.

Mycobacterium intracellulare is the most common cause of nontuberculous mycobacterial lung disease, with a rapidly growing prevalence worldwide. In this study, we performed comparative genomic analysis and antimicrobial susceptibility characteristics analysis of 117 clinical M. intracellulare strains in China. Phylogenetic analysis showed that clinical M. intracellulare strains had high genetic diversity and were not related to the geographical area. Notably, most strains (76.07%, 89/117) belonged to Mycobacterium paraintracellulare (MP) and Mycobacterium indicus pranii (MIP) in the genome, and we named them MP-MIP strains. These MP-MIP strains may be regarded as a causative agent of chronic lung disease. Furthermore, our data demonstrated that clarithromycin, amikacin, and rifabutin showed strong antimicrobial activity against both M. intracellulare and MP-MIP strains in vitro. Our findings also showed that there was no clear correlation between the rrs, rrl, and DNA gyrase genes (gyrA and gyrB) and the aminoglycosides, macrolides, and moxifloxacin resistance, respectively. In conclusion, this study highlights the high diversity of M. intracellulare in the clinical setting and suggests paying great attention to the lung disease caused by MP-MIP.

Safety evaluation and bioassay-guided isolation of antimycobacterial compounds from Morella salicifolia root ethanolic extract

Ethnopharmacological relevanceAlthough the available medicines can cure almost all tuberculosis drug-susceptible patients some problems including the emergence of multi-drug resistant and extensively drug-resistant strains press for the need of new anti-TB medicines. Morella salicifolia is a common plant that is widely used in traditional medicine for managing HIV and AIDS-related conditions including tuberculosis but no studies have been done to evaluate its safety and efficacy. Aim of the studyThis study was designed to investigate the antimycobacterial activity and safety of M. salicifolia extract and its constituents. Material and methodsAntimycobacterial activity of the crude extract was tested against non-pathogenic mycobacteria including Mycobacterium aurum (MA), Mycobacterium indicus pranii (MIP) and Mycobacterium madagascariense (MM) using the broth microdilution method. Bioassay-guided fractionation was employed to isolate the active compounds. Some of the isolated active compounds were tested for antimycobacterial activity against the standard and selected clinical isolates of M. tuberculosis. Safety of the crude extract was assessed using cytotoxicity assay and oral acute toxicity testing. ResultsThe crude extract exhibited antimycobacterial activity against all the species used. The study led to isolation of six compounds; four pentacyclic triterpenoids; (3β)-3-Hydroxyolean-12-en-28-oic acid (Oleanolic acid) (1), (2α,3β)-2,3-Dihydroxyolean-12-en-28-oic acid (maslinic acid) (2), D-Friedoolean-14-ene-3β,28-diol (taraxerol) (3), and D-Friedoolean-14-en-3β-ol (myricadiol) (4), and two diarylheptanoids; (±)-myricanol (5) and myricanone (6). The six compounds exhibited activity against three nonpathogenic mycobacteria species. Compound 2, was the most active, with MICs of 17, 28 and 56 μg/ml against MM, standard a M. tuberculosis strain H37RV and rifampicin resistant M. tuberculosis clinical isolates, respectively. The crude extract did not show toxicity on peripheral blood mononuclear cells and it was safe in mice following acute oral toxicity test. ConclusionThe results from this study indicate that some isolated compounds in Morella salicifolia could form potential scaffolds for drug development efforts targeting M. tuberculosis. More studies are needed to further explore the potential of the plant extract and its secondary metabolites in the management of HIV and AIDS-related conditions using in-vivo models.