<p>PMA stimulated THP1 cells were stimulated with 1 μg/ml Pam3CSK4 (Pam) and infected with 0.5 MOI of wild type HIV or Nef deficient HIV (HIVδNef) or Vpu deficient HIV (HIVδVpu) in the presence or absence of 20 μg/ml Rv3416 for 48h.... more
<p>PMA stimulated THP1 cells were stimulated with 1 μg/ml Pam3CSK4 (Pam) and infected with 0.5 MOI of wild type HIV or Nef deficient HIV (HIVδNef) or Vpu deficient HIV (HIVδVpu) in the presence or absence of 20 μg/ml Rv3416 for 48h. Cells were stained with Annexin V-APC. Thin lines represent stimulation with Pam3CSK4 alone and the thick lines represent stimulation as indicated. Data from one of three independent experiments are shown. Bar graphs show relative MFIs of the histograms. Data from one of three experiments are shown. P<0.03 for Pam vs Pam+Rv3416. P<0.04 for Pam vs Pam+HIV, P<0.03for Pam vs Pam+Rv3416+HIV.</p
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The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated... more
The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection. We report that activation of VGCC during infection synergistically downmodulates the generation of oxidative burst (ROS) by macrophages. This attenuation of ROS is regulated in a manner which is dependent on Toll like Receptor (TLR) and also on the route of calcium influx, Protein Kinase C (PKC) and by Mitogen Activation Protein Kinase (MAPK) pathways. VGCC activation during infection increase...
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<p>PMA stimulated THP1 cells were transfected with siRNA against MyD88, TRAF6, IRAK1, IRAK2 or IRAKM for 36h, followed by stimulation with 30 µg/ml of Rv3416 for 72h. L-type VGCC levels were monitored using flow cytometry. Bold... more
<p>PMA stimulated THP1 cells were transfected with siRNA against MyD88, TRAF6, IRAK1, IRAK2 or IRAKM for 36h, followed by stimulation with 30 µg/ml of Rv3416 for 72h. L-type VGCC levels were monitored using flow cytometry. Bold lines represent cells transfected with control siRNA followed by stimulations with Rv3416, while dotted lines represent cells transfected with specific siRNA to indicated molecules followed by stimulations with Rv3416. Thin lines represent unstimulated cells transfected with control siRNA. One of three independent experiments is shown. Bar chart shows the Fold increase in Mean Fluorescence Intensity (ΔMFI) in different groups over and above unstimulated control (represented as MOCK). Bars represent mean ± S.D. of three independent experiments.</p
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Staphylococcus aureus (S. aureus) is a gram-positive bacteria, which causes various fatal respiratory infections including pneumonia. The emergence of Methicillin-Resistance Staphylococcus aureus (MRSA) demands a thorough understanding of... more
Staphylococcus aureus (S. aureus) is a gram-positive bacteria, which causes various fatal respiratory infections including pneumonia. The emergence of Methicillin-Resistance Staphylococcus aureus (MRSA) demands a thorough understanding of host-pathogen interactions. Here we report the role of calcium in regulating defence responses of S. aureus in macrophages. Regulating calcium fluxes in cells by different routes differentially governs the expression of T cell costimulatory molecule CD80 and Th1 promoting IL-12 receptor. Inhibiting calcium influx from extracellular medium increased expression of IFN-γ and IL-10 while blocking calcium release from the intracellular stores inhibited TGF-β levels. Blocking voltage-gated calcium channels (VGCC) inhibited the expression of multiple cytokines. While VGCC regulated the expression of apoptosis protein Bax, extracellular calcium-regulated the expression of Cytochrome-C. Similarly, VGCC regulated the expression of autophagy initiator Beclin-...
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A key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing antigen processing... more
A key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing antigen processing and presentation, increasing leukocyte trafficking, inducing an anti-viral state, boosting the anti-microbial functions and affecting cellular proliferation and apoptosis. A complex interplay between immune cell activity and IFN-γ through coordinated integration of signals from other pathways involving cytokines and Pattern Recognition Receptors (PRRs) such as Interleukin (IL)-4, TNF-α, Lipopolysaccharide (LPS), Type-I Interferons (IFNS) etc. leads to initiation of a cascade of pro-inflammatory responses. Microarray data has unraveled numerous genes whose transcriptional regulation is influenced by IFN-γ. Consequently, IFN-γ stimulated cells display altered expression of many such target genes which mediate its downstream effector functions. The im...
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Research Interests: Immunology, Biology, Macrophages, Medicine, Signal Transduction, and 15 moreToll like receptor signaling, Mycobacterium tuberculosis, Mice, Animals, Membrane Fusion, Immune Evasion, Protein Domains, Molecular Mimicry, Bacterial Load, Primary Cell Culture, Lysosomes, Respiratory Burst, Gene Expression Regulation, Interleukin, and Interferon gamma
Antibiotic resistance can be a consequence of repeat-induced point (RIP) mutation and even by horizontal gene transfer in the pathogen genome for every chromosomal replication. On the account of a few vital antibiotic agents, point... more
Antibiotic resistance can be a consequence of repeat-induced point (RIP) mutation and even by horizontal gene transfer in the pathogen genome for every chromosomal replication. On the account of a few vital antibiotic agents, point mutation of chromosomally encoded proteins is the essential instrument for resistance. Another procedure that may add to the development of resistance in the course of treatment is adaptive or induced change. Notwithstanding RIP mutation, resistance may likewise be interceded by enzymes that change the antibiotic and the target protein or lessen the intracellular concentration of the antibiotics. These systems of resistance are dispersed between microscopic organisms by horizontal gene transfer. Drug resistance grants bacterial development in the nearness of an antibiotic; in any case, it is by all account not the only variable adding to treatment failure. The resistance is also reflected in cases wherein the antibiotic fails to clear the infection regardless of the absence of resistant microbes. These microbes are tolerant, and clinical reports advocate that the level of tolerance to treatment failure and mortality in a few diseases can be as crucial as the nature of antibiotic resistance. Intelligent methodologies and awareness of potential harmful effects of drugs will expect to promise continuous worldwide access to efficient antibiotics.
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We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulatingMycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that... more
We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulatingMycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expres-sion of VGCC-CACNA1S by Rv2463 andM. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demon-strate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dis-secting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression duringM. tb infection. Using siRNAs against molecular sen-sors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 indepe...
This section features outstanding photographs of clinical materials selected for their educational value or message, or possibly their rarity. The images are accompanied by brief case reports (limit 2 typed pages, 4 references). Our... more
This section features outstanding photographs of clinical materials selected for their educational value or message, or possibly their rarity. The images are accompanied by brief case reports (limit 2 typed pages, 4 references). Our readers are invited to submit items for consideration.
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Research Interests: Flow Cytometry, Calcium, Membrane Proteins, Macrophages, Transcription Factors, and 13 moreGene expression, Multidisciplinary, Signal Transduction, Tuberculosis, Mycobacterium tuberculosis, Reactive Oxygen Species, Mice, Female, Animals, Calcium channels, PLoS one, Respiratory Burst, and Cell Adhesion Molecules
Intravenous drug users (IDUs) and prisoners are groups of great interest in human immunodeficiency virus (HIV) infection and tuberculosis (TB) epidemiology. To determine predictors and temporal trends of the co-infection of Mycobacterium... more
Intravenous drug users (IDUs) and prisoners are groups of great interest in human immunodeficiency virus (HIV) infection and tuberculosis (TB) epidemiology. To determine predictors and temporal trends of the co-infection of Mycobacterium tuberculosis and HIV in IDUs on admission to prison. Between 1 January 1991 and 31 December 1997, 796 IDUs or former IDUs were studied. Socio-demographic and penitentiary variables were evaluated. HIV-positive patients with > or =5 mm induration on tuberculin test were deemed co-infected. Analysis of factors associated with co-infection was based on a logistic regression model. Of the incoming prisoners, 44.0% were infected by M. tuberculosis, 43.8% by HIV and 20.1% were co-infected. Co-infection predictors were: 1) total prison time served previously (none, OR 1; <2 years, OR 2.44, 95% CI 1.28-4.64; > or =2 years, OR 4.94, 95% CI 2.56-9.55); 2) age (16-25 years, OR 1; 25-29 years, OR 3.14, 95% CI 1.71-5.75; >29 years, OR 3.67, 95% CI 1....
Research Interests: Calcium, Macrophages, Adolescent, Apoptosis, Multidisciplinary, and 20 moreSignal Transduction, HIV, Spain, Toll like receptor signaling, Prisons, Tuberculosis, Humans, Mycobacterium tuberculosis, Female, Male, Coinfection, Incidence, PLoS one, Prevalence, Homeostasis, Adult, Antigens, Logistic Models, Respiratory Burst, and Gene Expression Regulation
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Research Interests: Calcium, Autophagy, Biological Chemistry, Dendritic Cells, Toll like receptor signaling, and 14 moreBiological Sciences, Mycobacterium tuberculosis, Reactive Oxygen Species, Mice, Immunity, Female, Animals, The, Superoxide Dismutase, CHEMICAL SCIENCES, T lymphocytes, Calmodulin, Respiratory Burst, and Cell Adhesion Molecules
The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated... more
The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection. We report that activation of VGCC during infection synergistically downmodulates the generation of oxidative burst (ROS) by macrophages. This attenuation of ROS is regulated in a manner which is dependent on Toll like Receptor (TLR) and also on the route of calcium influx, Protein Kinase C (PKC) and by Mitogen Activation Protein Kinase (MAPK) pathways. VGCC activation during infection increases cell survival and downmodulates autophagy. Concomi-tantly, pro-inflammatory responses such as IL-12 and IFN-γ secretion and the levels of their receptors on cell surface are inhibited. Finally, the ability of phagosomes to fuse with lysosomes in M. bovis BCG and M. tb H37Rv infected macrophages is also compromised when VGCC activation occurs during infection. The results point towards a well-orchestrated strategy adopted by mycobacteria to supress protective responses mounted by the host. This begins with the increase in the surface levels of VGCCs by mycobacteria and their antigens by well-controlled and regulated mechanisms. Subsequent activation of the upregulated VGCC following tweaking of calcium levels by molecular sensors in turn mediates suppressor responses and prepare the macrophages for long term persistent infection.