Publications by authors named "Javed N Agrewala"

72 Publications

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Deciphering the Structural Enigma of HLA Class-II Binding Peptides for Enhanced Immunoinformatics-based Prediction of Vaccine Epitopes.

J Proteome Res 2020 11 26;19(11):4655-4669. Epub 2020 Oct 26.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh 160036, India.

Vaccines remain the most efficacious means to avoid and eliminate morbid diseases associated with high morbidity and mortality. Clinical trials indicate the gaining impetus of peptide vaccines against diseases for which an effective treatment still remains obscure. CD4 T-cell-based peptide vaccines involve immunization with antigenic determinants from pathogens or neoplastic cells that possess the ability to elicit a robust T helper cell response, which subsequently activates other arms of the immune system. The available predictors of human leukocyte antigen II (HLA-II) binding peptides are sequence-based techniques, which ostensibly have balanced sensitivity and specificity. Structural analysis and understanding of the cognate peptide and HLA-II interactions are essential to empirically derive a successful peptide vaccine. However, the availability of structure-based epitope prediction algorithms is inadequate compared with sequence-based prediction methods. The present study is an attempt to understand the structural aspects of HLA-II binders by analyzing the Protein Data Bank (PDB) complexes of pHLA-II. Furthermore, we mimic the peptide exchange mechanism and demonstrate the structural implication of an acidic environment on HLA-II binders. Finally, we discuss a structure-guided approach to decipher potential HLA-II binders within an antigenic protein. This strategy may accurately predict the peptide epitopes and thus aid in designing successful peptide vaccines.
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http://dx.doi.org/10.1021/acs.jproteome.0c00405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640962PMC
November 2020

Intestinal microbiota disruption limits the isoniazid mediated clearance of Mycobacterium tuberculosis in mice.

Eur J Immunol 2020 12 29;50(12):1976-1987. Epub 2020 Jul 29.

Immunology Division, CSIR-Institute of Microbial Technology, Chandigarh, India.

Tuberculosis (TB) continues to remain a global threat due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and toxicity associated with TB drugs. Intestinal microbiota has been reported to affect the host response to immunotherapy and drugs. However, how it affects the potency of first-line TB drug isoniazid (INH) is largely unknown. Here, we examined the impact of gut microbial dysbiosis on INH efficiency to kill Mtb. In this study, we employed in vivo mouse model, pretreated with broad-spectrum antibiotics (Abx) cocktail to disrupt their intestinal microbial population prior to Mtb infection and subsequent INH therapy. We demonstrated that microbiota disruption results in the impairment of INH-mediated Mtb clearance, and aggravated TB-associated tissue pathology. Further, it suppressed the innate immunity and reduced CD4 T-cell response against Mtb. Interestingly, a distinct shift of gut microbial profile was noted with abundance of Enterococcus and reduction of Lactobacillus and Bifidobacterium population. Our results show that the intestinal microbiota is crucial determinant in efficacy of INH to kill Mtb and impacts the host immune response against infection. This work provides an intriguing insight into the potential links between host gut microbiota and potency of INH.
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http://dx.doi.org/10.1002/eji.202048556DOI Listing
December 2020

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against .

Front Immunol 2020 19;11:726. Epub 2020 May 19.

CSIR-Institute of Microbial Technology, Chandigarh, India.

The generation of enduring protective immunity by vaccines is of utmost importance. Intriguingly, there is considerable variation in the efficacy of vaccines amongst individuals. Various studies have shown that normal flora of gastrointestinal tract plays a vital role in maintaining host homeostasis and immunity. Since gut microbiome is also extremely variable between individuals, we speculate that it might impact individual's response to vaccines. Consequently, we administered broad spectrum antibiotics cocktail to induce gut dysbiosis and monitored its impact on the generation of long-lasting memory T cells and thereby BCG vaccine efficacy. Interestingly, gut dysbiosis significantly decreased the activation of CD4 T cells and CD8 T cells. Further, there was decline in the frequency of memory CD4 T cells and CD8 T cells in lungs and secondary lymphoid organs of the vaccinated animals. Moreover, it dampened the IFN-γ and TNF-α secretion and proliferation of -specific T cells. Most importantly, dysbiosis hampered clearance in vaccinated animals, as evidenced by increase in the colony forming units (CFUs) in lungs and spleen. Our findings indicate that gut dysbiosis can be one of the major factors responsible for variable efficacy of TB vaccines across the world.
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http://dx.doi.org/10.3389/fimmu.2020.00726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248201PMC
March 2021

Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory.

Front Immunol 2019 25;10:2441. Epub 2019 Oct 25.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

The gut microbiota significantly regulates the development and function of the innate and adaptive immune system. The attribute of immunological memory has long been linked only with adaptive immunity. Recent evidence indicates that memory is also present in the innate immune cells such as monocytes/macrophages and natural killer cells. These cells exhibit pattern recognition receptors (PRRs) that recognize microbe- or pathogen-associated molecular patterns (MAMPs or PAMPs) expressed by the microbes. Interaction between PRRs and MAMPs is quite crucial since it triggers the sequence of signaling events and epigenetic rewiring that not only play a cardinal role in modulating the activation and function of the innate cells but also impart a sense of memory response. We discuss here how gut microbiota can influence the generation of innate memory and functional reprogramming of bone marrow progenitors that helps in protection against infections. This article will broaden our current perspective of association between the gut microbiome and innate memory. In the future, this knowledge may pave avenues for development and designing of novel immunotherapies and vaccination strategies.
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http://dx.doi.org/10.3389/fimmu.2019.02441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842962PMC
November 2020

Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity.

Cancer Immunol Immunother 2019 Dec 5;68(12):1995-2004. Epub 2019 Nov 5.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

Glioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade gliomas, as confirmed by their CD68 and CD163 double-positive phenotype. In contrast, less M1 macrophages were noticed in high-grade gliomas, as evidenced by the down-regulation in the expression of CCL3 marker. In addition, we observed that higher gene expression ratio of CD163/CCL3 is associated with glioma progression. The Kaplan-Meier survival plots indicate that glioma patients with lower expression of M2c marker (CD163), and higher expression of M1 marker (CCL3) had better survival. Furthermore, we examined the systemic immune response in the peripheral blood and noted a predominance of M2 macrophages, myeloid-derived suppressor cells and PD-1 CD4 T cells in glioma patients. Thus, the study indicates a high gene expression ratio of CD163/CCL3 in high-grade gliomas as compared to low-grade gliomas and significantly elevated frequency of M2 macrophages and PD-1 CD4 T cells in the blood of tumor patients. These parameters could be used as an indicator of the early diagnosis and prognosis of the disease.
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http://dx.doi.org/10.1007/s00262-019-02423-8DOI Listing
December 2019

Induction of autophagy through CLEC4E in combination with TLR4: an innovative strategy to restrict the survival of .

Autophagy 2020 06 8;16(6):1021-1043. Epub 2019 Sep 8.

Immunology Division, CSIR-Institute of Microbial Technology , Chandigarh, India.

Host-directed therapies are gaining considerable impetus because of the emergence of drug-resistant strains of pathogens due to antibiotic therapy. Therefore, there is an urgent need to exploit alternative and novel strategies directed at host molecules to successfully restrict infections. The C-type lectin receptor CLEC4E and Toll-like receptor TLR4 expressed by host cells are among the first line of defense in encountering pathogens. Therefore, we exploited signaling of macrophages through CLEC4E in association with TLR4 agonists (C.T) to control the growth of (). We observed significant improvement in host immunity and reduced bacterial load in the lungs of infected mice and guinea pigs treated with C.T agonists. Further, intracellular killing of was achieved with a 10-fold lower dose of isoniazid or rifampicin in conjunction with C.T than the drugs alone. C.T activated MYD88, PtdIns3K, STAT1 and RELA/NFKB, increased lysosome biogenesis, decreased and gene expression and enhanced macroautophagy/autophagy. Macrophages from autophagy-deficient ( knockout or knockdown) mice showed elevated survival of . The present findings also unveiled the novel role of CLEC4E in inducing autophagy through MYD88, which is required for control of growth. This study suggests a unique immunotherapeutic approach involving CLEC4E in conjunction with TLR4 to restrict the survival of through autophagy.

Abbreviations: 3MA: 3 methyladenine; AO: acridine orange; Atg5: autophagy related 5; AVOs: acidic vesicular organelles; BECN1: beclin 1, autophagy related; BMDMs: bone marrow derived macrophages; bw: body weight; C.T: agonists of CLEC4E (C/TDB) and TLR4 (T/ultra-pure-LPS); CFU: colony forming unit; CLEC4E/Mincle: C-type lectin domain family 4, member e; CLR: c-type lectin receptor; INH: isoniazid; LAMP1: lysosomal-associated membrane protein 1; Mφ: infected C.T stimulated macrophages; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MDC: monodansylcadaverine; MTOR: mechanistic target of rapamycin kinase; MYD88: myeloid differentiation primary response 88; NFKB: nuclear factor of kappa light polypeptide gene enhance in B cells; NLR: NOD (nucleotide-binding oligomerization domain)-like receptors; PFA: paraformaldehyde; PPD: purified protein derivative; PtdIns3K: class III phosphatidylinositol 3-kinase; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RIF: rifampicin; RLR: retinoic acid-inducible gene-I-like receptors; TDB: trehalose-6,6´-dibehenate; TLR4: toll-like receptor 4; Ultra-pure-LPS: ultra-pure lipopolysaccharide-EK; V-ATPase: vacuolar-type H ATPase.
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http://dx.doi.org/10.1080/15548627.2019.1658436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469444PMC
June 2020

Gut Microbiota Regulates Mincle Mediated Activation of Lung Dendritic Cells to Protect Against .

Front Immunol 2019 28;10:1142. Epub 2019 May 28.

Immunology Division, CSIR-Institute of Microbial Technology, Chandigarh, India.

Gut microbial components serve as ligand for various pattern recognition receptors (PRRs) present on immune cells and thereby regulates host immunity. Dendritic cells (DCs) are highly specialized innate cells involved in immune response to () infection. The gut-lung axis is a potential therapeutic target in tuberculosis; however, understanding of the innate immune mechanism underlying the interaction of gut microbiota and lung still remains obscure. We investigated if antibiotics (Abx) induced gut dysbiosis is able to affect the activation of innate receptor, macrophage inducible C-type lectin (mincle) in lungs during infection. We found that dysbiosis reduced the lung mincle expression with a concomitant increase in survival. Further, Abx diminished the effector and memory T cell population, while elevating frequency of regulatory T cells (Tregs) in the lungs. Here, we show that dysbiotic mice exhibited low mincle expression on lung DCs. These DCs with impaired phenotype and functions had reduced ability to activate naïve CD4 T cells, and thus unable to restrict survival. administration of trehalose-6,6-dibehenate (TDB: mincle ligand) efficiently rescued this immune defect by enhancing lung DCs function and subsequent T cell response. Further, gut microbial profiling revealed augmentation of upon mincle stimulation in microbiota depleted animals. Accordingly, supplementation with restored mincle expression on lung DCs along with anti- response. Our data demonstrate that gut microbiota is crucial to maintain DC-dependent lung immune response against , mediated by mincle. Abx interrupt this process to induce impaired T cell-response and increased susceptibility to .
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http://dx.doi.org/10.3389/fimmu.2019.01142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558411PMC
August 2020

Curdlan Limits Survival Through STAT-1 Regulated Nitric Oxide Production.

Front Microbiol 2019 28;10:1173. Epub 2019 May 28.

Immunology Division, CSIR - Institute of Microbial Technology, Chandigarh, India.

Host-directed therapies have emerged as an innovative and promising approach in tuberculosis (TB) treatment due to the observed limitations of current TB regimen such as lengthy duration and emergence of drug resistance. Thus, we explored the role of curdlan (beta glucan polysaccharide) as a novel strategy to activate macrophages against (). The aim of the study was to investigate the role of curdlan in restricting the growth both and . Further, the immunomodulatory potential of curdlan against and the underlying mechanism is largely unknown. We found that curdlan treatment enhanced the antigen presentation, pro-inflammatory cytokines, uptake and killing activity of macrophages. studies showed that curdlan therapy significantly reduced the burden in lung and spleen of mice. Administration of curdlan triggered the protective Th1 and Th17 immunity while boosting the central and effector memory response in infected mice. Curdlan mediated anti- activity is through signal transducer and activator of transcription-1 (STAT-1), which regulates nitric oxide (NO) production through inducible NO synthase (iNOS) induction; along with this activation of nuclear factor kappa B (NF-κB) was also evident in infected macrophages. Thus, we demonstrate that curdlan exerts effective anti-tuberculous activity anti-tuberculous activity. It can be used as a potential host-directed therapy against .
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http://dx.doi.org/10.3389/fmicb.2019.01173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547911PMC
May 2019

A genomic analysis of Mycobacterium immunogenum strain CD11_6 and its potential role in the activation of T cells against Mycobacterium tuberculosis.

BMC Microbiol 2019 03 20;19(1):64. Epub 2019 Mar 20.

Microbial Type Culture Collection and Gene bank (MTCC), CSIR- Institute of Microbial Technology, Chandigarh, India.

Background: Mycobacterium tuberculosis (Mtb) is an etiological agent of tuberculosis (TB). Tuberculosis is a mounting problem worldwide. The only available vaccine BCG protects the childhood but not adulthood form of TB. Therefore, efforts are made continuously to improve the efficacy of BCG by supplementing it with other therapies. Consequently, we explored the possibility of employing Mycobacterium immunogenum (Mi) to improve BCG potential to protect against Mtb.

Results: We report here the genome mining, comparative genomics, immunological and protection studies employing strain CD11_6 of Mi. Mycobacterium immunogenum was isolated from duodenal mucosa of a celiac disease patient. The strain was whole genome sequenced and annotated for identification of virulent genes and other traits that may make it suitable as a potential vaccine candidate. Virulence profile of Mi was mapped and compared with two other reference genomes i.e. virulent Mtb strain H37Rv and vaccine strain Mycobacterium bovis (Mb) AFF2122/97. This comparative analysis revealed that Mi is less virulent, as compared to Mb and Mtb, and contains comparable number of genes encoding for the antigenic proteins that predict it as a probable vaccine candidate. Interestingly, the animals vaccinated with Mi showed significant augmentation in the generation of memory T cells and reduction in the Mtb burden.

Conclusion: The study signifies that Mi has a potential to protect against Mtb and therefore can be a future vaccine candidate against TB.
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http://dx.doi.org/10.1186/s12866-019-1421-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425668PMC
March 2019

ImmtorLig_DB: repertoire of virtually screened small molecules against immune receptors to bolster host immunity.

Sci Rep 2019 02 28;9(1):3092. Epub 2019 Feb 28.

Indian Institute of Technology Ropar, Rupnagar, 140001, India.

Host directed therapies to boost immunity against infection are gaining considerable impetus following the observation that use of antibiotics has become a continuous source for the emergence of drug resistant strains of pathogens. Receptors expressed by the cells of immune system play a cardinal role in initiating sequence of events necessary to ameliorate many morbid conditions. Although, ligands for the immune receptors are available; but their use is limited due to complex structure, synthesis and cost-effectiveness. Virtual screening (VS) is an integral part of chemoinformatics and computer-aided drug design (CADD) and aims to streamline the process of drug discovery. ImmtorLig_DB is a repertoire of 5000 novel small molecules, screened from ZINC database and ranked using structure based virtual screening (SBVS) against 25 immune receptors which play a pivotal role in defending and initiating the activation of immune system. Consequently, in the current study, small molecules were screened by docking on the essential domains present on the receptors expressed by cells of immune system. The screened molecules exhibited efficacious binding to immune receptors, and indicated a possibility of discovering novel small molecules. Other features of ImmtorLig_DB include information about availability, clustering analysis, and estimation of absorption, distribution, metabolism, and excretion (ADME) properties of the screened small molecules. Structural comparisons indicate that predicted small molecules may be considered novel. Further, this repertoire is available via a searchable graphical user interface (GUI) through http://bioinfo.imtech.res.in/bvs/immtor/ .
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http://dx.doi.org/10.1038/s41598-018-36179-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395627PMC
February 2019

Low prevalence of anti-xenobiotic antibodies among the occupationally exposed individuals is associated with a high risk of cancer.

Cancer Med 2019 01 21;8(1):246-260. Epub 2018 Dec 21.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

Cancer is one of the major health problem globally, responsible for high morbidity and mortality. Exposure of humans to xenobiotics is associated with the development of cancer. Further, these xenobiotics may combine with the body proteins and can act as a hapten and elicit an antibody response. In this study, we examined whether the regular exposer to xenobiotics evokes anti-xenobiotic antibodies and the presence of these antibodies have any correlation with the prevention of cancer. Interestingly, we noticed that the healthy household contacts showed significantly greater titers of anti-xenobiotic antibodies, as compared to cancer patients. Consequently, suggesting that the higher level of anti-xenobiotic antibodies may be responsible for neutralizing the effect of xenobiotics in the healthy subjects. Thereby, preventing the individuals from disease. In contrast, the presence of a significantly lower level of anti-xenobiotic antibodies in the cancer patients may be a causative factor for disease infliction. In conclusion, immunotherapy employing anti-xenobiotic antibodies may provide a prudent remedial measure to clear xenobiotics from the body of the individuals and thereby protecting from cancer.
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http://dx.doi.org/10.1002/cam4.1773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346253PMC
January 2019

A lipidated bi-epitope vaccine comprising of MHC-I and MHC-II binder peptides elicits protective CD4 T cell and CD8 T cell immunity against Mycobacterium tuberculosis.

J Transl Med 2018 10 11;16(1):279. Epub 2018 Oct 11.

CSIR-Institute of Microbial Technology, Chandigarh, India.

Background: The clinical trials conducted at Chingleput India suggest that BCG fails to protect against tuberculosis (TB) in TB-endemic population. Recent studies advocate that non-tuberculous mycobacteria and latent Mycobacterium tuberculosis (Mtb) infection interferes in the antigen processing and presentation of BCG in inducing protective immunity against Mtb. Thereby, indicating that any vaccine that require extensive antigen processing may not be efficacious in TB-endemic zones. Recently, we have demonstrated that the vaccine candidate L91, which is composed of lipidated promiscuous MHC-II binder epitope, derived from latency associated Acr1 antigen of Mtb is immunogenic in the murine and Guinea pig models of TB and conferred better protection than BCG against Mtb.

Methods: In this study, we have used a multi-stage based bi-epitope vaccine, namely L4.8, comprising of MHC-I and MHC-II binding peptides of active (TB10.4) and latent (Acr1) stages of Mtb antigens, respectively. These peptides were conjugated to the TLR-2 agonist Pam2Cys.

Results: L4.8 significantly elicited both CD8 T cells and CD4 T cells immunity, as evidenced by increase in the enduring polyfunctional CD8 T cells and CD4 T cells. L4.8 efficiently declined Mtb-burden and protected animals better than BCG and L91, even at the late stage of Mtb infection.

Conclusions: The BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. This study emphatically denotes that L4.8 can be a promising future vaccine candidate for controlling active and latent TB.
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http://dx.doi.org/10.1186/s12967-018-1653-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180631PMC
October 2018

TLR-3 Stimulation Skews M2 Macrophages to M1 Through IFN-αβ Signaling and Restricts Tumor Progression.

Front Immunol 2018 19;9:1650. Epub 2018 Jul 19.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

During tumor progression, macrophages shift their protective M1-phenotype to pro-tumorigenic M2-subtype. Therefore, conversion of M2 to M1 phenotype may be a potential therapeutic intervention. TLRs are important pathogen recognition receptors expressed by cells of the immune system. Recently, a crucial role of TLR-3 has been suggested in cancer. Consequently, in the current study, we defined the role of TLR-3 in the reversion of M2-macrophages to M1. We analyzed the role of TLR-3 stimulation for skewing M2-macrophages to M1 at mRNA and protein level through qRT-PCR, flow cytometry, western blotting, and ELISA. The effectiveness of TLR-3L stimulation to revert M2-macrophages to M1 was evaluated in the murine tumor model. To determine the role of IFN-αβ signaling and , we used macrophages and anti-IFN-αβ antibodies, respectively. We observed upregulation of M1-specific markers MHC-II and costimulatory molecules like CD86, CD80, and CD40 on M2-macrophages upon TLR-3 stimulation. In contrast, reduced expression of M2-indicators CD206, , and pro-inflammatory cytokines was noticed. The administration of TLR-3L in the murine tumor reverted the M2-macrophages to M1-phenotype and regressed the tumor growth. The mechanism deciphered for macrophage reversion and controlling the tumor growth is dependent on IFN-αβ signaling pathway. The results indicate that the signaling through TLR-3 is important in protection against tumors by skewing M2-macrophages to protective M1-subtype.
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http://dx.doi.org/10.3389/fimmu.2018.01650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060442PMC
July 2018

A Facile Approach for Synthesis and Intracellular Delivery of Size Tunable Cationic Peptide Functionalized Gold Nanohybrids in Cancer Cells.

Bioconjug Chem 2018 04 13;29(4):1102-1110. Epub 2018 Mar 13.

CSIR-Institute of Microbial Technology , Chandigarh - 160036 , India.

Peptide-based drug delivery systems have become a mainstay in the contemporary medicinal field, resulting in the design and development of better pharmaceutical formulations. However, most of the available reports employ tedious multiple reaction steps for the conjugation of bioactive cationic peptides with drug delivery vehicles. To overcome these limitations, the present work describes a one-step approach for facile and time efficient synthesis of highly cationic cell penetrating peptide functionalized gold nanoparticles and their intracellular delivery. The nanoconstruct was synthesized by the reduction of gold metal ions utilizing cell penetrating peptide (CPP), which facilitated the simultaneous synthesis of metal nanoparticles and the capping of the peptide over the nanoparticle surface. The developed nanoconstruct was thoroughly characterized and tested for intracellular delivery into HeLa cells. Intriguingly, a high payload of cationic peptide over gold particles was achieved, in comparison to conventional conjugation methods. Moreover, this method also provides the ability to control the size and peptide payload of nanoparticles. The nanoconstructs produced showed enhanced cancer cell penetration (μM) and significant cytotoxic effect compared to unlabeled gold nanoparticles. Therefore, this novel approach may also have significant future potential to kill intracellular hidden dreaded pathogens like the human immunodeficiency virus, Mycobacterium tuberculosis, and so forth.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00772DOI Listing
April 2018

Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis.

Front Immunol 2018 9;9:193. Epub 2018 Feb 9.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

The mononuclear phagocyte system (MPS) constitutes dendritic cells, monocytes, and macrophages. This system contributes to various functions that are essential for maintaining homeostasis, activation of innate immunity, and bridging it with the adaptive immunity. Consequently, MPS is highly important in bolstering immunity against the pathogens. However, MPS is the frontline cells in destroying (), yet the bacterium prefers to reside in the hostile environment of macrophages. Therefore, it may be very interesting to study the struggle between and MPS to understand the outcome of the disease. In an event when MPS predominates , the host remains protected. By contrast, the situation becomes devastating when the pathogen tames and tunes the host MPS, which ultimately culminates into tuberculosis (TB). Hence, it becomes extremely crucial to reinvigorate MPS functionality to overwhelm and eliminate it. In this article, we discuss the strategies to bolster the function of MPS by exploiting the molecules associated with the innate immunity and highlight the mechanisms involved to overcome the -induced suppression of host immunity. In future, such approaches may provide an insight to develop immunotherapeutics to treat TB.
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http://dx.doi.org/10.3389/fimmu.2018.00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811511PMC
April 2019

Morbid Sequences Suggest Molecular Mimicry between Microbial Peptides and Self-Antigens: A Possibility of Inciting Autoimmunity.

Front Microbiol 2017 9;8:1938. Epub 2017 Oct 9.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

Understanding etiology of autoimmune diseases has been a great challenge for designing drugs and vaccines. The pathophysiology of many autoimmune diseases may be attributed to molecular mimicry provoked by microbes. Molecular mimicry hypothesizes that a sequence homology between foreign and self-peptides leads to cross-activation of autoreactive T cells. Different microbial proteins are implicated in various autoimmune diseases, including multiple sclerosis, human type 1 diabetes, primary biliary cirrhosis and rheumatoid arthritis. It may be imperative to identify the microbial epitopes that initiate the activation of autoreactive T cells. Consequently, in the present study, we employed immunoinformatics tools to delineate homologous antigenic regions between microbes and human proteins at not only the sequence level but at the structural level too. Interestingly, many cross-reactive MHC class II binding epitopes were detected from an array of microbes. Further, these peptides possess a potential to skew immune response toward Th1-like patterns. The present study divulges many microbial target proteins, their putative MHC-binding epitopes, and predicted structures to establish the fact that both sequence and structure are two important aspects for understanding the relationship between molecular mimicry and autoimmune diseases. Such findings may enable us in designing potential immunotherapies to tolerize autoreactive T cells.
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http://dx.doi.org/10.3389/fmicb.2017.01938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640720PMC
October 2017

A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity.

J Transl Med 2017 10 6;15(1):201. Epub 2017 Oct 6.

CSIR-Institute of Microbial Technology, Chandigarh, India.

Background: The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice.

Methods: In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA.

Results: Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44CD62LCD127) and effector memory (CD44CD62LCD127) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γTNF-α) and Th17 cells (IFN-γIL-17A) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91.

Conclusions: Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against Mtb. This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.
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http://dx.doi.org/10.1186/s12967-017-1301-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389088PMC
October 2017

Bolstering Immunity through Pattern Recognition Receptors: A Unique Approach to Control Tuberculosis.

Front Immunol 2017 2;8:906. Epub 2017 Aug 2.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

The global control of tuberculosis (TB) presents a continuous health challenge to mankind. Despite having effective drugs, TB still has a devastating impact on human health. Contributing reasons include the emergence of drug-resistant strains of , the AIDS-pandemic, and the absence of effective vaccines against the disease. Indeed, alternative and effective methods of TB treatment and control are urgently needed. One such approach may be to more effectively engage the immune system; particularly the frontline pattern recognition receptor (PRR) systems of the host, which sense pathogen-associated molecular patterns (PAMPs) of . It is well known that 95% of individuals infected with in latent form remain healthy throughout their life. Therefore, we propose that clues can be found to control the remainder by successfully manipulating the innate immune mechanisms, particularly of nasal and mucosal cavities. This article highlights the importance of signaling through PRRs in restricting entry and subsequently preventing its infection. Furthermore, we discuss whether this unique therapy employing PRRs in combination with drugs can help in reducing the dose and duration of current TB regimen.
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http://dx.doi.org/10.3389/fimmu.2017.00906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539433PMC
August 2017

Diametric Role of the Latency-Associated Protein Acr1 of in Modulating the Functionality of Pre- and Post-maturational Stages of Dendritic Cells.

Front Immunol 2017 30;8:624. Epub 2017 May 30.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

It is instrumental for the to persist within its host in dormancy. represses most of its metabolic machinery during latency, but upregulates the expression of latency-associated protein alpha-crystallin protein (Acr1). Therefore, it is imperative to understand how throughout dormancy, employs Acr1 to regulate the host immunity. This study reveals that Acr1 exhibits divergent effect on the pre- and post-maturation stages of dendritic cells (DCs). In the current study, we demonstrate that early encounter of bone marrow cells with Acr1 while differentiating into DCs (AcrDC), leads to impairment in their maturation. In contrast, when exposed to Acr1 after maturation (AcrDC), DCs show augmentation in their activity, secretion of TNF-α, IL-12, IL-6, and activation of T cells. Additionally, AcrDC promoted the polarization of naïve CD4 T cells to Th1 cells and Th17 cells and restricted the intracellular growth of . Furthermore, these DCs upregulated the expression of CCR7 and exhibited enhanced migratory capabilities. The discrete impact of Acr1 on DCs is mediated through a mechanism involving STAT-1, SOCS-3, ERK, TLR-4, and NF-κB signaling pathways. This study reveals the unprecedented role of Acr1 in distinctly modulating the function of DCs at different stages of maturation.
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http://dx.doi.org/10.3389/fimmu.2017.00624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447689PMC
May 2017

Antibody response against PhoP efficiently discriminates among healthy individuals, tuberculosis patients and their contacts.

PLoS One 2017 20;12(3):e0173769. Epub 2017 Mar 20.

CSIR-Institute of Microbial Technology, Chandigarh, India.

Tuberculosis continues to be one of the most devastating global health problem. Its diagnosis will benefit in timely initiation of the treatment, cure and therefore reduction in the transmission of the disease. Tests are available, but none can be comprehensively relied on for its diagnosis; especially in TB-endemic zones. PhoP is a key player in Mycobacterium tuberculosis virulence but nothing has been known about its role in the diagnosis of TB. We monitored the presence of anti-PhoP antibodies in the healthy, patients and their contacts. In addition, we also measured antibodies against early secretory antigens ESAT-6 and CFP-10, and latency associated antigen Acr-1 to include proteins that are associated with the different stages of disease progression. Healthy subjects showed high antibody titer against PhoP than patients and their contacts. In addition, a distinct pattern in the ratio of Acr-1/PhoP was observed among all cohorts. This study for the first time demonstrates a novel role of anti-PhoP antibodies, as a possible marker for the diagnosis of TB and therefore will contribute in the appropriate action and management of the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358785PMC
August 2017

Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide.

Sci Rep 2016 12 21;6:39492. Epub 2016 Dec 21.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, 160036, India.

IFN alfacon-1 (Infergen) is a synthetic form of Interferon (IFN)-α2b. Infergen has immunomodulatory activity and is effective against hepatitis C virus. However, the effect of Infergen (IFG) on Mycobacterium tuberculosis (Mtb) has not yet been reported. Therefore, for the first time, we have studied the influence of IFG in constraining the survival of Mtb in human macrophages. We observed that IFG significantly enhanced the maturation and activation of macrophages. Further, it substantially augmented the secretion of IL-6, nitric oxide (NO) and antigen uptake. Moreover, macrophages exhibited remarkably higher bactericidal activity, as evidenced by reduction in the Mtb growth. Infergen-mediated mechanism was different from the type-1 interferons; since it worked through the activation of NF-κB, phosphorylation of STAT-3 and Akt-PI3K that improved the bactericidal activity through autophagy and NO release. In future, IFG immunotherapy can be a novel strategy for treating patients and controlling TB.
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http://dx.doi.org/10.1038/srep39492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175149PMC
December 2016

Alteration in the Gut Microbiota Provokes Susceptibility to Tuberculosis.

Front Immunol 2016 28;7:529. Epub 2016 Nov 28.

Immunology Division, CSIR-Institute of Microbial Technology , Chandigarh , India.

The microbiota that resides in the gastrointestinal tract provides essential health benefits to the host. In particular, they regulate immune homeostasis. Recently, several evidences indicate that alteration in the gut microbial community can cause infectious and non-infectious diseases. Tuberculosis (TB) is the most devastating disease, inflicting mortality and morbidity. It remains unexplored, whether changes in the gut microbiota can provoke or prevent TB. In the current study, we have demonstrated the antibiotics driven changes in the gut microbial composition and their impact on the survival of () in the lungs, liver, and spleen of infected mice, compared to those with intact microbiota. Interestingly, dysbiosis of microbes showed significant increase in the bacterial burden in lungs and dissemination of to spleen and liver. Furthermore, elevation in the number of Tregs and decline in the pool of IFN-γ- and TNF-α-releasing CD4 T cells was noticed. Interestingly, fecal transplantation in the gut microbiota disrupted animals exhibited improved Th1 immunity and lesser Tregs population. Importantly, these animals displayed reduced severity to infection. This study for the first time demonstrated the novel role of gut microbes in the susceptibility to TB and its prevention by microbial implants. In future, microbial therapies may help in treating patients suffering from TB.
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http://dx.doi.org/10.3389/fimmu.2016.00529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124573PMC
November 2016

Genome sequencing, assembly, annotation and analysis of  strain DMB3-Bh1 reveals genes responsible for pathogenicity.

Gut Pathog 2016 8;8:55. Epub 2016 Nov 8.

Immunology Laboratory, CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh, 160036 India.

Background: is coagulase-negative staphylococci (CNS), found occasionally on the skin of humans but recurrently on other mammals. Recent reports suggest that this commensal bacterium may cause diseases in humans and other animals. In this study, we present the first report of whole genome sequencing of strain DMB3-Bh1, which was isolated from the stool of a mouse.

Results: The draft genome of strain DMB3-Bh1 consisted of 2,81,0255 bp with G+C content of 32.7 mol%, 2623 predicted coding sequences (CDSs) and 58 RNAs. The final assembly contained 12 contigs of total size 2,81,0255 bp with N50 contig length of 4,37,962 bp and the largest contig assembled measured 7,61,338 bp. Further, an interspecies comparative genomic analysis through rapid annotation using subsystem technology server was achieved with RF122 that revealed 36 genes having similarity with DMB3-Bh1. 35 genes encoded for virulence, disease and defense and 1 gene encoded for phages, prophages and transposable elements.

Conclusions: These results suggest co linearity in genes between DMB3-Bh1 and RF122 that contribute to pathogenicity and might be the result of horizontal gene transfer. The study indicates that DMB3-Bh1 may be a potential emerging pathogen for rodents.
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http://dx.doi.org/10.1186/s13099-016-0139-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101723PMC
November 2016

Stimulation through CD40 and TLR-4 Is an Effective Host Directed Therapy against .

Front Immunol 2016 27;7:386. Epub 2016 Sep 27.

CSIR-Institute of Microbial Technology , Chandigarh , India.

Tuberculosis (TB) is the leading cause of morbidity and mortality among all infectious diseases. Failure of as a vaccine and serious side-effects and toxicity due to long-term TB drug regime are the major hurdles associated with TB control. The problem is further compounded by the emergence of drug-resistance strains of (). Consequently, it demands a serious attempt to explore safer and superior treatment approaches. Recently, an improved understanding of host-pathogen interaction has opened up new avenues for immunotherapy for treating TB. Although, dendritic cells (DCs) show a profound role in generating immunity against , their immunotherapeutic potential needs to be precisely investigated in controlling TB. Here, we have devised an approach of bolstering DCs efficacy against by delivering signals through CD40 and TLR-4 molecules. We found that DCs triggered through CD40 and TLR-4 showed increased secretion of IL-12, IL-6, and TNF-α. It also augmented autophagy. Interestingly, CD40 and TLR-4 stimulation along with the suboptimal dose of anti-TB drugs significantly fortified their efficacy to kill . Importantly, animals treated with the agonists of CD40 and TLR-4 boosted Th1 and Th17 immunity. Furthermore, it amplified the pool of memory CD4 T cells as well as CD8 T cells. Furthermore, substantial reduction in the bacterial burden in the lungs was observed. Notably, this adjunct therapy employing immunomodulators and chemotherapy can reinvigorate host immunity suppressed due to drugs and . Moreover, it would strengthen the potency of drugs in curing TB.
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http://dx.doi.org/10.3389/fimmu.2016.00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037235PMC
September 2016

Erratum to: Genome sequencing, annotation and comparative genomic analysis of Shigella dysenteriae strain SD1D.

Gut Pathog 2016 10;8:38. Epub 2016 Aug 10.

Microbial Type Culture Collection and Gene Bank, CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh, 160036 India.

[This corrects the article DOI: 10.1186/1757-4749-6-28.].
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http://dx.doi.org/10.1186/s13099-016-0120-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980780PMC
August 2016

Triggering through NOD-2 Differentiates Bone Marrow Precursors to Dendritic Cells with Potent Bactericidal activity.

Sci Rep 2016 06 6;6:27263. Epub 2016 Jun 6.

CSIR-Institute of Microbial Technology, Chandigarh, 160036, INDIA.

Dendritic cells (DCs) play a crucial role in bridging innate and adaptive immunity by activating naïve T cells. The role of pattern recognition receptors like Toll-Like Receptors and Nod-Like Receptors expressed on DCs is well-defined in the recognition of the pathogens. However, nothing is precisely studied regarding the impact of NOD-2 signaling during the differentiation of DCs. Consequently, we explored the role of NOD-2 signaling in the differentiation of DCs and therefore their capability to activate innate and adaptive immunity. Intriguingly, we observed that NOD-2 stimulated DCs (nDCs) acquired highly activated and matured phenotype and exhibited substantially greater bactericidal activity by robust production of nitric oxide. The mechanism involved in improving the functionality of nDCs was dependent on IFN-αβ signaling, leading to the activation of STAT pathways. Furthermore, we also observed that STAT-1 and STAT-4 dependent maturation and activation of DCs was under the feedback mechanism of SOCS-1 and SOCS-3 proteins. nDCs acquired enhanced potential to activate chiefly Th1 and Th17 immunity. Taken together, these results suggest that nDCs can be exploited as an immunotherapeutic agent in bolstering host immunity and imparting protection against the pathogens.
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http://dx.doi.org/10.1038/srep27263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893688PMC
June 2016

A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host.

Sci Rep 2016 Apr 7;6:23917. Epub 2016 Apr 7.

CSIR-Institute of Microbial Technology, Chandigarh, India.

Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ(+)TNF-α(+) polyfunctional Th1 cells and IL-17A(+)IFN-γ(+) Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime.
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http://dx.doi.org/10.1038/srep23917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823727PMC
April 2016

Innate Immunity Holding the Flanks until Reinforced by Adaptive Immunity against Mycobacterium tuberculosis Infection.

Front Microbiol 2016 14;7:328. Epub 2016 Mar 14.

Council of Scientific and Industrial Research - Institute of Microbial Technology Chandigarh, India.

T cells play a cardinal role in imparting protection against Mycobacterium tuberculosis (Mtb). However, ample time is required before T-cells are able to evoke efficient effector responses in the lung, where the mycobacterium inflicts disease. This delay in T cells priming, which is termed as lag phase, provides sufficient time for Mtb to replicate and establish itself within the host. In contrast, innate immunity efficiently curb the growth of Mtb during initial phase of infection through several mechanisms. Pathogen recognition by innate cells rapidly triggers a cascade of events, such as apoptosis, autophagy, inflammasome formation and nitric oxide production to kill intracellular pathogens. Furthermore, bactericidal mechanisms such as autophagy and apoptosis, augment the antigen processing and presentation, thereby contributing substantially to the induction of adaptive immunity. This manuscript highlights the role of innate immune mechanisms in restricting the survival of Mtb during lag phase. Finally, this article provides new insight for designing immuno-therapies by targeting innate immune mechanisms to achieve optimum immune response to cure TB.
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http://dx.doi.org/10.3389/fmicb.2016.00328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789502PMC
March 2016

Signaling through NOD-2 and TLR-4 Bolsters the T cell Priming Capability of Dendritic cells by Inducing Autophagy.

Sci Rep 2016 Jan 12;6:19084. Epub 2016 Jan 12.

CSIR-Institute of Microbial Technology, Chandigarh-160036, India.

T cells play a cardinal role in mediating protection against intracellular pathogens like Mycobacterium tuberculosis (Mtb). It is important to understand the factors that govern the T cell response; thereby can modulate its activity. Dendritic cells (DCs) are the major player in initiation and augmentation of T cell response. Targeting DCs to induce their optimum maturation and activation can lead to a better T cell response. Interestingly, we observed that combinatorial signaling of DCs through NOD-2 and TLR-4 fortified better yield of IL-12p40/70, IL-6 and IFN-γ and upregulated the expression of CD40, CD80 and CD86 costimulatory molecules. Further, we noticed improved phagocytic capabilities of DCs. Furthermore, NOD-2 and TLR-4 induced autophagy in DCs, which enhanced the activation of T cells. This study signifies that NOD-2 and TLR-4 exhibit synergism in invigorating the activity of DCs. Consequently, this strategy may have significant immunotherapeutic potential in bolstering the function of DCs and thus improving the immunity against pathogens.
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http://dx.doi.org/10.1038/srep19084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709561PMC
January 2016