scholarly journals Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Lanbo Shi ◽  
Qingkui Jiang ◽  
Yuri Bushkin ◽  
Selvakumar Subbian ◽  
Sanjay Tyagi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Cells ◽  
Aerobic Glycolysis ◽  
Defense Responses ◽  
Bioactive Lipids ◽  
Macrophage Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Metabolic Switch ◽  
Content Type ◽  
M1 Polarization

ABSTRACT Macrophages are the primary targets of Mycobacterium tuberculosis infection; the early events of macrophage interaction with M. tuberculosis define subsequent progression and outcome of infection. M. tuberculosis can alter the innate immunity of macrophages, resulting in suboptimal Th1 immunity, which contributes to the survival, persistence, and eventual dissemination of the pathogen. Recent advances in immunometabolism illuminate the intimate link between the metabolic states of immune cells and their specific functions. In this review, we describe the little-studied biphasic metabolic dynamics of the macrophage response during progression of infection by M. tuberculosis and discuss their relevance to macrophage immunity and M. tuberculosis pathogenicity. The early phase of macrophage infection, which is marked by M1 polarization, is accompanied by a metabolic switch from mitochondrial oxidative phosphorylation to hypoxia-inducible factor 1 alpha (HIF-1α)-mediated aerobic glycolysis (also known as the Warburg effect in cancer cells), as well as by an upregulation of pathways involving oxidative and antioxidative defense responses, arginine metabolism, and synthesis of bioactive lipids. These early metabolic changes are followed by a late adaptation/resolution phase in which macrophages transition from glycolysis to mitochondrial oxidative metabolism, with a consequent dampening of macrophage proinflammatory and antimicrobial responses. Importantly, the identification of upregulated metabolic pathways and/or metabolic regulatory mechanisms with immunomodulatory functions during M1 polarization has revealed novel mechanisms of M. tuberculosis pathogenicity. These advances can lead to the development of novel host-directed therapies to facilitate bacterial clearance in tuberculosis by targeting the metabolic state of immune cells.

scholarly journals Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

2015 ◽  
Vol 83 (3) ◽  
pp. 1217-1223 ◽  
Author(s):  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
William C. Gause ◽  
Padmini Salgame
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Regulatory Cells ◽  
Helminth Infection ◽  
Treg Cells ◽  
Helminth Species ◽  
Nippostrongylus Brasiliensis ◽  
T Regulatory Cell ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type

Previously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.

scholarly journals Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01422-20
Author(s):  
Harindra D. Sathkumara ◽  
Karyna Hansen ◽  
Socorro Miranda-Hernandez ◽  
Brenda Govan ◽  
Catherine M. Rush ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mycobacterium Tuberculosis ◽  
Disease Burden ◽  
Low Dose ◽  
Diabetic Mice ◽  
Antidiabetic Drug ◽  
Mycobacterium Tuberculosis Infection ◽  
Therapeutic Concentration ◽  
Content Type

ABSTRACTComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic individuals.

scholarly journals Efficient 5-OP-RU-Induced Enrichment of Mucosa-Associated Invariant T Cells in the Murine Lung Does Not Enhance Control of Aerosol Mycobacterium tuberculosis Infection

2020 ◽  
Vol 89 (1) ◽  
pp. e00524-20 ◽  
Author(s):  
Charles Kyriakos Vorkas ◽  
Olivier Levy ◽  
Miroslav Skular ◽  
Kelin Li ◽  
Jeffrey Aubé ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Bacterial Load ◽  
Cell Subset ◽  
Mycobacterium Tuberculosis Infection ◽  
Class I Mhc ◽  
Content Type ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosa-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved major histocompatibility complex class I (MHC I)-related molecule, MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosol Mycobacterium tuberculosis infection in mice. Intranasal costimulation with the lipopeptide Toll-like receptor (TLR)2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in the lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early after M. tuberculosis challenge, these MAIT cells did not restrict M. tuberculosis bacterial load. MAIT cells were depleted by the onset of the adaptive immune response, with decreased detection of granzyme B+ and gamma interferon (IFN-γ)+ MAIT cells relative to that in uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in nitric oxide synthase 2 (NOS2)-deficient mice all failed to reveal an effect of P2C/5-OP-RU-induced MAIT cells on M. tuberculosis control. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion after M. tuberculosis exposure, without attenuating M. tuberculosis growth, suggesting that MAIT cell enrichment in the lung is not sufficient to control M. tuberculosis infection.

scholarly journals Transcriptional Profiling of Mycobacterium tuberculosis Exposed toIn VitroLysosomal Stress

2016 ◽  
Vol 84 (9) ◽  
pp. 2505-2523 ◽  
Author(s):  
Wenwei Lin ◽  
Paola Florez de Sessions ◽  
Garrett Hor Keong Teoh ◽  
Ahmad Naim Nazri Mohamed ◽  
Yuan O. Zhu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Metabolic Reprogramming ◽  
Human Macrophage ◽  
Host Immune System ◽  
Activated Macrophages ◽  
Intrinsic Resistance ◽  
Macrophage Infection ◽  
Content Type

Increasing experimental evidence supports the idea thatMycobacterium tuberculosishas evolved strategies to survive within lysosomes of activated macrophages. To further our knowledge ofM. tuberculosisresponse to the hostile lysosomal environment, we profiled the global transcriptional activity ofM. tuberculosiswhen exposed to the lysosomal soluble fraction (SF) prepared from activated macrophages. Transcriptome sequencing (RNA-seq) analysis was performed using various incubation conditions, ranging from noninhibitory to cidal based on the mycobacterial replication or killing profile. Under inhibitory conditions that led to the absence of apparent mycobacterial replication,M. tuberculosisexpressed a unique transcriptome with modulation of genes involved in general stress response, metabolic reprogramming, respiration, oxidative stress, dormancy response, and virulence. The transcription pattern also indicates characteristic cell wall remodeling with the possible outcomes of increased infectivity, intrinsic resistance to antibiotics, and subversion of the host immune system. Among the lysosome-specific responses, we identified theglgE-mediated 1,4 α-glucan synthesis pathway and a defined group of VapBC toxin/anti-toxin systems, both of which represent toxicity mechanisms that potentially can be exploited for killing intracellular mycobacteria. A meta-analysis including previously reported transcriptomic studies in macrophage infection andin vitrostress models was conducted to identify overlapping and nonoverlapping pathways. Finally, the Tap efflux pump-encoding geneRv1258cwas selected for validation. AnM. tuberculosis ΔRv1258cmutant was constructed and displayed increased susceptibility to killing by lysosomal SF and the antimicrobial peptide LL-37, as well as attenuated survival in primary murine macrophages and human macrophage cell line THP-1.

scholarly journals Evaluation of Gamma Interferon Immune Response Elicited by the Newly Constructed PstS-1(285-374):CFP10 Fusion Protein To Detect Mycobacterium tuberculosis Infection

2014 ◽  
Vol 21 (4) ◽  
pp. 552-560 ◽  
Author(s):  
Leonardo Silva de Araujo ◽  
Fernanda Carvalho de Queiroz Mello ◽  
Nidai de Bárbara Moreira da Silva ◽  
Janaina Aparecida Medeiros Leung ◽  
Silvia Maria Almeida Machado ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Positive Tuberculin Skin Test ◽  
Gamma Interferon ◽  
Preventative Treatment ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Ifn Γ ◽  
First Time

ABSTRACTThe PstS1 antigen is highly immunogenic, principally when combined with CFP10 during both latent and active TB infection. In the present study, a selectedpstS1gene fragment was cloned, fused with CFP10, and expressed inEscherichia coli. The product [PstS-1(285-374):CFP10] was compared to the recombinant fused RD1 (region of deletion 1) protein (ESAT-6:CFP10) in detectingMycobacterium tuberculosisinfection in 108 recent contacts of pulmonary tuberculosis (TB) cases, considering a positive tuberculin skin test (TST) to be the baseline. The release of gamma interferon (IFN-γ) in 22-h whole-blood and 5-day lymphocyte stimulation assays primed with each antigen was determined. All contacts were clinically followed for up to 1 year, and 87% of the tuberculin skin test-positive (TSTpositive) patients accepted preventative treatment. Concerning the IFN-γ response to PstS-1(285-374):CFP10 in the 22-h and 5-day assays, a slight increase in contact-TSTpositivedetection was observed (23/54 and 26/54) compared to the level seen with the RD1 protein (18/54 and 24/54) whereas in the TSTnegativegroup, similarly lower numbers (≤5/48) of responders were achieved for both antigens, except for RD1 in the 5-day assay (8/48). By combining the IFN-γ responders to both antigens in the 5-day assays, slightly higher increases in positivity were found in the TSTpositive(32/54) and TSTnegative(10/48) groups. Two of 12 untreated TSTpositivecontacts progressed to active TB and were concordantly positive in all assays, except for one contact who lacked positivity in the RD1 5-day assay. We demonstrated for the first time that PstS-1(285-374):CFP10 slightly increased contact positivity and detection of active disease progression, suggesting its potential application as a TB infection marker.

scholarly journals Acute Inflammation Confers Enhanced Protection against Mycobacterium tuberculosis Infection in Mice

2021 ◽  
Author(s):  
Tucker J. Piergallini ◽  
Julia M. Scordo ◽  
Paula A. Pino ◽  
Larry S. Schlesinger ◽  
Jordi B. Torrelles ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Causative Agent ◽  
Acute Inflammation ◽  
Causes Of Death ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
High Level ◽  
Tuberculosis Disease

Mycobacterium tuberculosis , the causative agent of tuberculosis disease, is estimated to infect one-fourth of the world’s population and is one of the leading causes of death due to an infectious disease worldwide. The high-level variability in tuberculosis disease responses in the human populace may be linked to immune processes related to inflammation.

scholarly journals The Endothelin System Has a Significant Role in the Pathogenesis and Progression of Mycobacterium tuberculosis Infection

2014 ◽  
Vol 82 (12) ◽  
pp. 5154-5165 ◽  
Author(s):  
Andre F. Correa ◽  
Alexandre M. Bailão ◽  
Izabela M. D. Bastos ◽  
Ian M. Orme ◽  
Célia M. A. Soares ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Host Interactions ◽  
Endothelin System ◽  
Etb Receptor ◽  
The Impact ◽  
The Relationship ◽  
Host Tissues

ABSTRACTTuberculosis (TB) remains a major global health problem, and although multiple studies have addressed the relationship betweenMycobacterium tuberculosisand the host on an immunological level, few studies have addressed the impact of host physiological responses. Proteases produced by bacteria have been associated with important alterations in the host tissues, and a limited number of these enzymes have been characterized in mycobacterial species.M. tuberculosisproduces a protease called Zmp1, which appears to be associated with virulence and has a putative action as an endothelin-converting enzyme. Endothelins are a family of vasoactive peptides, of which 3 distinct isoforms exist, and endothelin 1 (ET-1) is the most abundant and the best-characterized isoform. The aim of this work was to characterize the Zmp1 protease and evaluate its role in pathogenicity. Here, we have shown thatM. tuberculosisproduces and secretes an enzyme with ET-1 cleavage activity. These data demonstrate a possible role of Zmp1 for mycobacterium-host interactions and highlights its potential as a drug target. Moreover, the results suggest that endothelin pathways have a role in the pathogenesis ofM. tuberculosisinfections, and ETA or ETB receptor signaling can modulate the host response to the infection. We hypothesize that a balance between Zmp1 control of ET-1 levels and ETA/ETB signaling can allowM. tuberculosisadaptation and survival in the lung tissues.

scholarly journals Accuracy of QuantiFERON-TB Gold Plus Test for Diagnosis of Mycobacterium tuberculosis Infection in Children

2020 ◽  
Vol 58 (6) ◽  
Author(s):  
Danilo Buonsenso ◽  
Giovanni Delogu ◽  
Clelia Perricone ◽  
Roberta Grossi ◽  
Angela Careddu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Infection ◽  
Cross Sectional Study ◽  
Mycobacterium Tuberculosis Infection ◽  
Cross Sectional ◽  
Content Type ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Microbiological Analyses ◽  
Active Disease

ABSTRACT Compared to its predecessor QuantiFERON-TB Gold In Tube (QFT-IT), QuantiFERON-TB Gold Plus (QFT-Plus) contains an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T cells. The ability to discriminate CD4+ and CD8+ responses is suggested to be useful in differentiating stages of Mycobacterium tuberculosis infection. While QFT-Plus has already been evaluated in adults, there are not enough data in children evaluated for suspected active tuberculosis (TB) or latent TB infection (LTBI). A prospective cross-sectional study was conducted among children aged 0 to 17 years who were evaluated for suspected active TB or screened for LTBI. All children underwent QFT-Plus and further clinical, radiological, and/or microbiological analyses according to clinical scenario. Of the 198 children enrolled, 43 (21.7%) were tested because of suspicion of active TB. A total of 12/43 (27.9%) were diagnosed with active TB, and among these, 10/12 (83.3%) had a positive QFT-Plus assay. Of the 155 children screened for LTBI, 18 (11.6%) had a positive QFT-Plus, and 5 (2.5%) had an indeterminate result. TB1 and TB2 quantitative responses were not able to discriminate active disease from latent infection. The percent agreement between TB1 and TB2 was 100%. QFT-Plus assay showed good sensitivity for active TB and was particularly useful for the evaluation of children with suspected LTBI, giving a low rate of indeterminate results in this group. More studies are needed to properly evaluate QFT-Plus ability in discriminating active disease from latent infection.

scholarly journals Antibody-Secreting Cells To Diagnose Mycobacterium tuberculosis Infection in Children in Pakistan

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Najeeha Talat Iqbal ◽  
Kumail Ahmed ◽  
Farah N. Qamar ◽  
Fariha Shaheen ◽  
Aisha Mehnaz ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Serum Antibody ◽  
Preventive Therapy ◽  
Case Definition ◽  
Major Advance ◽  
Mycobacterium Tuberculosis Infection ◽  
Secreting Cell ◽  
Content Type ◽  
Antibody Secreting Cell ◽  
Pediatric Tuberculosis

ABSTRACT Reliance on microbiologic methods to diagnose Mycobacterium tuberculosis infection is a suboptimal approach for children due in part to the paucibacillary nature of the disease. A blood-based biomarker assay, such as the mycobacterial-antibody-secreting cell (MASC) assay, could be a major advance for the field of study of pediatric tuberculosis (TB). Children <15 years of age with clinical concern for TB and age-matched children with no concern for TB were enrolled from outpatient clinics in Karachi, Pakistan. MASC, ferritin, and C-reactive protein (CRP) assays were performed, and results were compared among cases and controls, as well as among children with a case definition of “confirmed TB,” “probable TB,” or “possible TB.” MASC responses were significantly higher among children with TB than among controls (0.41 optical density [OD] versus 0.28 OD, respectively, P < 0.001), and the differences were largely driven by the data from children with confirmed TB (P = 0.002). Ferritin and CRP values were significantly higher among those with confirmed TB than among those with the other disease states and controls (P = 0.004 and P = 0.019, respectively). The use of the MASC assay as a blood-based biomarker for TB disease shows some promise among children with microbiologically confirmed disease; however, the performance characteristics for the majority of young children with unconfirmed TB were suboptimal in this cohort. IMPORTANCE Tuberculosis (TB) in children represents a missed opportunity for diagnosis and preventive therapy. The magnitude or burden of disease in children is not fully understood due to our limitations with respect to exploring sensitive diagnostic algorithms. In a setting of TB endemicity in Pakistan, we carried out a proof-of-concept study to evaluate for the first time the performance of B cell analyses by the use of well-defined diagnostic criteria and NIH consensus guidelines as “culture-confirmed,” “probable,” and “possible” TB groups. In contrast to detection of serum antibody, we focused on mycobacterial-antibody-secreting cell (MASC) detection as a marker of active disease in children with a strong suspicion of TB. Further work exploring a larger panel of inflammatory biomarkers and enrichment of B cells with the objective of increasing the sensitivity of the current MASC assay would lead to the development of a field-friendly assay for timely diagnosis of childhood TB.

scholarly journals Laboratory Diagnosis of Mycobacterium tuberculosis Infection and Disease in Children

2016 ◽  
Vol 54 (6) ◽  
pp. 1434-1441 ◽  
Author(s):  
James J. Dunn ◽  
Jeffrey R. Starke ◽  
Paula A. Revell
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Infection ◽  
Laboratory Diagnosis ◽  
Molecular Tools ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Advanced Technologies ◽  
Tuberculosis In Children ◽  
Immunodiagnostic Tests ◽  
Tuberculosis Disease

Diagnosis of tuberculosis in children is challenging; even with advanced technologies, the diagnosis is often difficult to confirm microbiologically in part due to the paucibacillary nature of the disease. Clinical diagnosis lacks standardization, and traditional and molecular microbiologic methods lack sensitivity, particularly in children. Immunodiagnostic tests may improve sensitivity, but these tests cannot distinguish tuberculosis disease from latent infection and some lack specificity. While molecular tools like Xpert MTB/RIF have advanced our ability to detectMycobacterium tuberculosisand to determine antimicrobial resistance, decades old technologies remain the standard in most locales. Today, the battle against this ancient disease still poses one of the primary diagnostic challenges in pediatric laboratory medicine.

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