ABSTRACT
Acinetobacter baumannii (A. baumannii) is one of the major representative aetiologies of recalcitrant nosocomial infections. Genotypic and phenotypic alterations in A. baumannii have resulted in a significant surge in multidrug resistance (MDR). Of all the factors responsible for the development of antimicrobial resistance (AMR), efflux protein pumps play a paramount role. In pursuit of a safe alternative for the prevention and control of A. baumannii infections, bioactive compounds from the aerial parts of the medicinal plant Artemisia pallens were studied. GC-MS analysis of the ethanol extract of A. pallens detected five major compounds: lilac alcohol A, spathulenol, lilac alcohol C, n-hexadecanoic acid, and vulgarin. In silico examinations were performed using the Schrödinger suite. Homology modelling was performed to predict the structure of the efflux protein of A. baumannii-LAC-4 strain (MDR Ab-EP). The identified bioactive compounds were analysed for their binding efficiency with MDR Ab-EP. High binding efficiency was observed with vulgarin with a glide score of -4.775 kcal/mol and stereoisomers of lilac alcohol A (-3.706 kcal/mol) and lilac alcohol C (-3.706 kcal/mol). Our molecular dynamic simulation studies unveiled the stability of the ligand-efflux protein complex. Vulgarin and lilac alcohol A possessed strong and stable binding efficiency with MDR Ab-EP. Furthermore, validation of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the ligands strongly suggested that these compounds could serve as a lead molecule in the development of an alternate drug from A. pallens.
Subject(s)
Acinetobacter baumannii , Artemisia , Acinetobacter baumannii/metabolism , Anti-Bacterial Agents/chemistry , Artemisia/metabolism , Bacterial Proteins/metabolism , Drug Resistance, Multiple, Bacterial , Ligands , Microbial Sensitivity TestsABSTRACT
Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1Mut)-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1Mut were sufficiently robust to cause a strong physiological outcome in vitro and in vivo. cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS.
ABSTRACT
Biofilm-producing Staphylococcus aureus (S. aureus) is less sensitive to conventional antibiotics than free-living planktonic cells. Here, we evaluated the antibiofilm activity of Illicium verum (I. verum) and one of its constituent compounds 3-hydroxybenzoic acid (3-HBA) against multi-drug-resistant S. aureus. We performed gas chromatography-mass spectroscopy (GC-MS) to identify the major constituents in the methanolic extract of I. verum. Ligand-receptor interactions were studied by molecular docking, and in vitro investigations were performed using crystal violet assay, spreading assay, hemolysis, proteolytic activity, and growth curve analysis. The methanolic extract of I. verum inhibited S. aureus at 4.8 mg/mL, and GC-MS analysis revealed anethole, m-methoxybenzaldehyde, and 3-HBA as the major constituents. Molecular docking attributed the antibiofilm activity to an active ligand present in 3-HBA, which strongly interacted with the active site residues of AgrA and SarA of S. aureus. At a subinhibitory concentration of 2.4 mg/mL, the extract showed biofilm inhibition. Similarly, 3-HBA inhibited biofilm activity at 25 µg/mL (90.34%), 12.5 µg/mL (77.21%), and 6.25 µg/mL (62.69%) concentrations. Marked attrition in bacterial spreading was observed at 2.4 mg/mL (crude extract) and 25 µg/mL (3-HBA) concentrations. The methanol extract of I. verum and 3-HBA markedly inhibited ß-hemolytic and proteolytic activities of S. aureus. At the lowest concentration, the I. verum extract (2.4 mg/mL) and 3-HBA (25 µg/mL) did not inhibit bacterial growth. Optical microscopy and SEM analysis confirmed that I. verum and 3-HBA significantly reduced biofilm dispersion without disturbing bacterial growth. Together, we found that the antibiofilm activity of I. verum and 3-HBA strongly targeted the Agr and Sar systems of S. aureus.
ABSTRACT
COVID-19 is being extensively studied, and much remains unknown regarding the long-term consequences of the disease on immune cells. The different arms of the immune system are interlinked, with humoral responses and the production of high-affinity antibodies being largely dependent on T cell immunity. Here, we longitudinally explored the effect COVID-19 has on T cell populations and the virus-specific T cells, as well as neutralizing antibody responses, for 6-7 months following hospitalization. The CD8+ TEMRA and exhausted CD57+CD8+ T cells were markedly affected with elevated levels that lasted long into convalescence. Further, markers associated with T-cell activation were upregulated at the inclusion, and in the case of CD69+CD4+ T cells this lasted all through the study duration. The levels of T cells expressing negative immune checkpoint molecules were increased in COVID-19 patients and sustained for a prolonged duration following recovery. Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19. Our study revealed significant and long-term alterations in T cell populations and key events associated with COVID-19 pathogenesis.
ABSTRACT
BackgroundThe magnitude of protection conferred after recovery from COVID-19 or by vaccine administration, and the duration of protective immunity developed, remains ambiguous. MethodsWe investigated the factors associated with antibody decay in 519 individuals who received treatment for COVID-19-related illness or received COVID-19 vaccination with two commercial vaccines, viz., an adenoviral vector-based (AZD1222) and a whole-virion-based inactivated (BBV152) vaccine in Chennai, India from March 2021. Blood samples collected during regular follow-up post-infection/vaccination andwere examined for anti-SARS-CoV-2 IgG by a commercial automated chemiluminescent immunoassay (CLIA). ResultsAge and underlying comorbidities were the two variables that were independently associated with the development of breakthrough infection. Individuals who were >60 years of age with underlying comorbid conditions had a [~]15 times and [~]10 times greater risk for developing a breakthrough infection and hospitalization, respectively. The time elapsed since the first booster dose was associated with attrition in anti-SARS-CoV-2 IgG, where each month passed was associated with an ebb in the neutralizing antibody levels by a coefficient of -6 units. ConclusionsOur findings advocate that the elderly with underlying comorbidities require a second booster dose with AZD1222 and BBV152.
ABSTRACT
Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like T cells that bridge between innate and adaptive immunity. MAIT cells act like a 'biliary firewall' protecting the epithelial lining of the liver against pathogenic intruders. MAIT1 and MAIT17 subsets respond rapidly to pathogenic presence both in the liver as well as in the peripheral circulation. In addition to chronic hepatitis B virus (HBV) infection, MAIT cells also appear to serve as potential therapeutic targets in several other chronic ailments. Evidence indicates that MAIT cells have tissue repair functions also paving way for fibrotic changes during chronic HBV infection. Observations also suggest that HBV-hepatitis delta virus (HDV) co-infection disease progression is closely associated with loss of MAIT cells. Furthermore, reduction in the number of hepatic MAIT cells in patients with cirrhotic non-alcoholic fatty liver disease and HBV-associated primary liver cancer has also been reported. Given their concrete role against HBV disease progression, and has also become evident that the tumor microenvironment can cause functional impairment of MAIT cells. Here, we reviewed the protective and the pathological role of MAIT cells in chronic HBV infection and certain other related medical conditions based on the understanding that an optimal functioning of the MAIT cell arsenal is key to a "host-friendly" immune defense against HBV disease progression.
Subject(s)
Hepatitis B, Chronic , Mucosal-Associated Invariant T Cells , Hepatitis B virus , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Humans , Lymphocyte CountABSTRACT
Chromobacterium violaceum (C. violaceum) is a Gram-negative, rod-shaped facultatively anaerobic bacterium implicated with recalcitrant human infections. Here, we evaluated the anti-QS and antibiofilm activities of ethyl acetate extracts of Passiflora edulis (P. edulis) on the likely inactivation of acyl-homoserine lactone (AHL)-regulated molecules in C. violaceum both by in vitro and in silico analyses. Our investigations showed that the sub-MIC levels were 2, 1, and 0.5 mg/mL, and the concentrations showed a marked reduction in violacein pigment production by 75.8, 64.6, and 35.2%. AHL quantification showed 72.5, 52.2, and 35.9% inhibitions, inhibitions of EPS production (72.8, 36.5, and 25.9%), and reductions in biofilm formation (90.7, 69.4, and 51.8%) as compared to a control. Light microscopy and CLSM analysis revealed dramatic reduction in the treated biofilm group as compared to the control. GC-MS analysis showed 20 major peaks whose chemical structures were docked as the CviR ligand. The highest docking score was observed for hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester bonds in the active site of CviR with a binding energy of -8.825 kcal/mol. Together, we found that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester remarkably interacted with CviR to inhibit the QS system. Hence, we concluded that hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester of P. edulis could likely be evaluated for treating C. violaceum infections.
ABSTRACT
Burkholderia pseudomallei is the causative agent for melioidosis. Because of its intracellular nature, the bacterium is capable of replicating within a plethora of eukaryotic cell lines. B. pseudomallei can remain dormant within host cells without symptoms for years, causing recrudescent infections. Here, we investigated the pathogenesis mechanism behind the suppression of T cell responses by B. pseudomallei . Peripheral blood mononuclear cells (1×106 cells/well) isolated by Ficoll Paque (Sigma-Aldrich) density gradient centrifugation were incubated with optimized concentrations of bacterial crude culture filtrate antigens (CFAs) (10 ug ml-1) and heat-killed bacteria [1â:â10 multiplicity of infection (m.o.i.)]. Following incubation, cells were investigated for surface expression of coinhibitory molecules by flow cytometry. We found that B. pseudomallei induced the upregulation of programmed death 1 (PD-1), a molecule responsible for T cell exhaustion, on T cells in vitro following exposure to crude CFAs of B. pseudomallei . This upregulation of PD-1 probably contributes to poor immune surveillance and disease pathogenesis.
ABSTRACT
Mucosa-associated invariant T (MAIT) cells are recently characterized as a novel subset of innate-like T cells that recognize microbial metabolites as presented by the MHC-1b-related protein MR1. The significance of MAIT cells in anti-bacterial defense is well-understood but not clear in viral infections such as SIV/HIV infection. Here we studied the phenotype, distribution, and function of MAIT cells and their association with plasma viral levels during chronic SHIV infection in rhesus macaques (RM). Two groups of healthy and chronic SHIV-infected macaques were characterized for MAIT cells in blood and mucosal tissues. Similar to human, we found a significant fraction of macaque T cells co-expressing MAIT cell markers CD161 and TCRVα-7.2 that correlated directly with macaque MR1 tetramer. These cells displayed memory phenotype and expressed high levels of IL-18R, CCR6, CD28, and CD95. During chronic infection, the frequency of MAIT cells are enriched in the blood but unaltered in the rectum; both blood and rectal MAIT cells displayed higher proliferative and cytotoxic phenotype post-SHIV infection. The frequency of MAIT cells in blood and rectum correlated inversely with plasma viral RNA levels and correlated directly with total CD4 T cells. MAIT cells respond to microbial products during chronic SHIV infection and correlated positively with serum immunoreactivity to flagellin levels. Tissue distribution analysis of MAIT cells during chronic infection showed significant enrichment in the non-lymphoid tissues (lung, rectum, and liver) compared to lymphoid tissues (spleen and LN), with higher levels of tissue-resident markers CD69 and CD103. Exogenous in vitro cytokine treatments during chronic SHIV infection revealed that IL-7 is important for the proliferation of MAIT cells, but IL-12 and IL-18 are important for their cytolytic function. Overall our results demonstrated that MAIT cells are enriched in blood but unaltered in the rectum during chronic SHIV infection, which displayed proliferative and functional phenotype that inversely correlated with SHIV plasma viral RNA levels. Treatment such as combined cytokine treatments could be beneficial for enhancing functional MAIT cells during chronic HIV infection in vivo.
Subject(s)
Disease Susceptibility , HIV Infections/etiology , HIV Infections/metabolism , HIV/immunology , Mucosal-Associated Invariant T Cells/physiology , Simian Acquired Immunodeficiency Syndrome/etiology , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Immunodeficiency Virus/immunology , Animals , Biomarkers , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Lymphocyte Count , Macaca mulatta , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Virus Diseases/immunology , Animals , CD8-Positive T-Lymphocytes/virology , Chronic Disease , Humans , Virus Diseases/virologyABSTRACT
Hepatitis C virus (HCV) represents a challenging global health threat to ~200 million infected individuals. Clinical data suggest that only ~10â»15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
ABSTRACT
Immune reconstitution inflammatory syndrome (IRIS) continues to be a complication in HIV/tuberculosis (TB) co-infected patients initiating highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the risk factors associated with developing IRIS to identify a possible biomarker to predict or diagnose IRIS in patients initiating HAART. A total of 175 HIV/TB co-infected patients initiating HAART were followed up longitudinally during September 2010 to May 2013 attending a HIV care clinic in Chennai. Patients were followed up longitudinally after HAART initiation and baseline demographic, laboratory parameters and treatment characteristics between patients with IRIS events and those without IRIS events were compared. Chi-square or Fisher's exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables were performed using SPSS, version 12.0 software. Patients with IRIS had a significantly lower median baseline CD4+ T-cell count (P = 0.0039). There were no differences in terms of sex, CD4 T-cell %, plasma viral load, time interval between initiating ATT and HAART between the IRIS and non-IRIS patients. Low CD4+ T-cell count (<100 cells/µL) could be used as a marker to screen and monitor patients initiating HAART.
Subject(s)
Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/adverse effects , HIV Infections/complications , HIV Infections/drug therapy , Immune Reconstitution Inflammatory Syndrome/epidemiology , Tuberculosis/complications , Adult , CD4 Lymphocyte Count , Female , Follow-Up Studies , Humans , India/epidemiology , Male , Prospective Studies , Risk Factors , Sex Distribution , Viral LoadABSTRACT
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes chikungunya infection in humans. Despite the widespread distribution of CHIKV, no antiviral medication or vaccine is available against this virus. Therefore, it is crucial to find an effective compound to combat CHIKV. We aimed to predict the possible interactions between non-structural protein 3 (nsP) of CHIKV as one of the most important viral elements in CHIKV intracellular replication and 3 potential flavonoids using a computational approach. The 3-dimensional structure of nsP3 was retrieved from the Protein Data Bank, prepared and, using AutoDock Vina, docked with baicalin, naringenin and quercetagetin as ligands. The first-rated ligand with the strongest binding affinity towards the targeted protein was determined based on the minimum binding energy. Further analysis was conducted to identify both the active site of the protein that reacts with the tested ligands and all of the existing intermolecular bonds. Compared to the other ligands, baicalin was identified as the most potential inhibitor of viral activity by showing the best binding affinity (-9.8 kcal/mol). Baicalin can be considered a good candidate for further evaluation as a potentially efficient antiviral against CHIKV.
Subject(s)
Antiviral Agents/pharmacology , Chikungunya virus/chemistry , Chromones/pharmacology , Flavanones/pharmacology , Flavonoids/pharmacology , Molecular Docking Simulation , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Binding Sites , Chikungunya virus/metabolism , Chromones/chemistry , Flavanones/chemistry , Flavones , Flavonoids/chemistry , Protein Binding , Viral Nonstructural Proteins/metabolismABSTRACT
Moraxella catarrhalis, a less virulent microorganism that colonizes the upper respiratory tract, has recently been associated with lower respiratory disease, especially in HIV-positive immunocompromised individuals and children. Here, we correlated the DNA clustering pattern of 24 clinical isolates of M. catarrhalis for ß-lactamase production and drug resistance, from different disease groups using three different arbitrarily selected primers, P1 (5'-TCACGATGCA-3'), P14 (5'-GATCAAGTCC-3') and P17 (5'-GATCTGACAC-3'). M. catarrhalis revealed three distinct banding patterns with primer P1, four with P14 and P17. 71% (n = 17) of the isolates revealed pattern 2 with primer P1, which discriminated majority (12/21) of the isolates grouped under the major branch of the dendrogram. The minor branch had only three isolates. Separation of M. catarrhalis into two subpopulations (major and minor clusters) with primer P1 is suggestive of diverse genetic lineage. A high level of concordance between RAPD and antibiotic profile was observed. Clustering of M. catarrhalis recovered from different disease groups reflect the identical clinical background or the common geographical/temporal factors. The presence or absence of ß-lactamase in a cluster confirmed their single source of origin.
Subject(s)
DNA Fingerprinting/methods , Molecular Typing/methods , Moraxella catarrhalis/classification , Moraxella catarrhalis/genetics , Moraxellaceae Infections/microbiology , Random Amplified Polymorphic DNA Technique/methods , Cluster Analysis , DNA Primers/genetics , Drug Resistance, Bacterial , Genetic Variation , Genotype , Humans , Moraxella catarrhalis/isolation & purification , beta-Lactamases/metabolismABSTRACT
Colony morphology variation is a characteristic of Burkholderia pseudomallei primary clinical isolates, associated with variations in expression of virulence factors. Here, we performed comparative investigations on adhesion, invasion, plaque-forming abilities and protein profiles of B. pseudomallei wild-type (WT) and a small colony variant (SCV). The percentage of SCV adherence to A549 cells was significantly higher (2.73%) than WT (1.91%). In contrast, WT was significantly more efficient (0.63%) than SCV (0.31%) in invasiveness and in inducing cellular damage. Using 2-DE and MALDI TOF/TOF, 263 and 258 protein spots were detected in WT and SCV, respectively. Comparatively, 49 proteins were differentially expressed in SCV when compared with WT. Of these, 31 proteins were up-regulated, namely, nucleoside diphosphate kinase (Ndk), phosphoglycerate kinase (Pgk), thioredoxin (TrxA), putative ferritin DPS-family DNA-binding protein (DPS) and oxidoreductase (AhpC) that are known to be involved in adhesion, intracellular survival and persistence. However, among the 18 down-regulated proteins, enolase (Eno), elongation factor (EF-Tu) and universal stress-related proteins were associated with invasion and virulence. Differences observed in these protein profiles provide ample clues to their association with the morphotypic and phenotypic characteristics of colony variants, providing additional insights into the potential association of B. pseudomallei colony morphotypes with disease pathogenesis. BIOLOGICAL SIGNIFICANCE: Comparative analyses were performed on the ability of wild-type and small colony variant of B. pseudomallei to adhere, invade and form plaques on human epithelial cells. In addition, proteomic analysis of these different colony morphotypes was also carried out. This research provides insights into the virulence and pathogenesis attributes of B. pseudomallei and contributes to better understand the pathogenesis of melioidosis.
Subject(s)
Burkholderia pseudomallei/cytology , Epithelial Cells/microbiology , Gene Expression Regulation, Bacterial , Virulence Factors/metabolism , Bacterial Adhesion , Bacterial Proteins/metabolism , Biomarkers/metabolism , Burkholderia pseudomallei/pathogenicity , Cell Line, Tumor , Databases, Protein , Gene Expression Profiling , Humans , Mass Spectrometry , Melioidosis/microbiology , Proteome , Proteomics , Virulence/geneticsABSTRACT
Early defence mechanisms of innate immunity respond rapidly to infection against HIV-1 in the genital mucosa. Additionally, innate immunity optimises effective adaptive immune responses against persistent HIV infection. Recent research has highlighted the intrinsic roles of apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G, tripartite motif-containing protein 5, tetherin, sterile α-motif and histidine/aspartic acid domain-containing protein 1 in restricting HIV-1 replication. Likewise, certain endogenously secreted antimicrobial peptides, namely α/ß/θ-defensins, lactoferrins, secretory leukocyte protease inhibitor, trappin-2/elafin and macrophage inflammatory protein-3α are reportedly protective. Whilst certain factors directly inhibit HIV, others can be permissive. Interferon-λ3 exerts an anti-HIV function by activating Janus kinase-signal transducer and activator of transcription-mediated innate responses. Morphine has been found to impair intracellular innate immunity, contributing to HIV establishment in macrophages. Interestingly, protegrin-1 could be used therapeutically to inhibit early HIV-1 establishment. Moreover, chloroquine inhibits plasmacytoid dendritic cell activation and improves effective T-cell responses. This minireview summarizes the recently identified targets for innate immunity-mediated therapies and outlines the challenges that lie ahead in improving treatment of HIV infection.
Subject(s)
HIV Infections/immunology , HIV Infections/therapy , HIV-1/immunology , Immunity, Innate , Immunologic Factors/pharmacology , Immunotherapy/methods , Humans , Immunologic Factors/administration & dosageABSTRACT
Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3), T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules.
Subject(s)
Dendritic Cells/virology , HIV-1/immunology , Lymphocyte Activation/immunology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunology , T-Lymphocytes/immunology , p38 Mitogen-Activated Protein Kinases/metabolism , Cell Proliferation/drug effects , Cytosol/drug effects , Cytosol/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/pathology , Enterotoxins/pharmacology , HIV-1/drug effects , Humans , Immunologic Memory/drug effects , Interleukin-10/metabolism , Interleukin-6/metabolism , Lymphocyte Activation/drug effects , MAP Kinase Signaling System/drug effects , Neutralization Tests , Signal Transduction/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/enzymology , T-Lymphocytes/pathologyABSTRACT
The mechanisms behind certain co-morbid conditions associated with chronic HIV disease still remain elusive. HIV-associated peripheral neuropathy is one among those rarely studied manifestations in HIV-1 infection. Numerous underlying factors associated with peripheral neuropathy have been described in HIV disease. Herein, we hypothesized certain heretofore undescribed potential mechanisms that lead to HIV associated neuropathy. Being a multifactoral manifestation, HIV-associated neuropathy is presumed to have an association with physiological factors namely, adrenal inadequacy/steroid resistance and lipodystrophy-induced cushion-effect loss in peripheral nerves. Therefore, management of the adrenals with steroids at the time-point of high inflammatory burden thereby preventing lipodystrophy by selecting the optimum treatment regimen could markedly alleviate the severity of HIV-associated neuropathic manifestations.