Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4β1–Expressing Immune Cells

Mattila, Joshua T.; Beaino, Wissam; Maiello, Pauline; Coleman, M. Teresa; White, Alexander G.; Scanga, Charles A.; Flynn, JoAnne L.; Anderson, Carolyn J.

doi:10.4049/jimmunol.1700231

Cited by 46 publications

(58 citation statements)

References 45 publications

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“…Furthermore, the use of targeted approaches, including those visualizing inflammatory nodules in experimental mycobacterial infections, can provide insight into the metabolic flux within tissue microenvironments. For example, by using a fluorescent glucose analog, such as 2-deoxy-2-[ 18 F]-fluoro-D glucose, paired with positron emission tomography, glucose use within tissue microenvironments can be determined (42). In addition, 2-deoxy-2-[ 18 F]-fluoro-D glucose and positron emission tomography have been used to identify active granulomas and track treatment efficacy in TB patients (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

Lange

McKell

Schmidt

et al. 2019

The Journal of Immunology

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Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline–generating (i.e., iNOS) and l-citrulline–using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.

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Section: Discussionmentioning

confidence: 99%

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

Lange

McKell

Schmidt

et al. 2019

The Journal of Immunology

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“…Similar observations have been made in nonhuman primates, the animal model that most closely resembles human TB . This model has further contributed to the field by allowing observations of granulomas as dynamic structures that fluctuate in size and characteristics over time and the identification of all the various types of granulomas (regression, progression calcification) that can occur in the same individual and independently of disease severity . The findings suggest that local rather than systemic immune responses determine the outcome of M. tuberculosis infection at a specific site and contradict the simplistic view of granulomas as a static phenomenon.…”

Section: What Tb Models Are Relevant Models For Extraction Of Large Dmentioning

confidence: 63%

Addressing diversity in tuberculosis using multidimensional approaches

Lerm

Dockrell

2018

J Intern Med

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Tuberculosis is a complex disease, which can affect many organs other than the lungs. Initial infection may be cleared without inducing immunological memory, or progress directly to primary disease. Alternatively, the infection may be controlled as latent TB infection, that may progress to active tuberculosis at a later stage. There is now a greater understanding that these infection states are part of a continuum, and studies using PET/CT imaging have shown that individual lung granulomas may respond to infection independently, in an un-synchronized manner. In addition, the Mycobacterium tuberculosis organisms themselves can exist in different states: as nonculturable forms, as 'persisters', as rapidly growing bacteria and a biofilm-forming cording phenotype. The 'omics' approaches of transcriptomics, metabolomics and proteomics can help reveal the mechanisms underlying these different infection states in the host, and identify biosignatures with diagnostic potential, that can predict the development of disease, in 'progressors' as early as 12-18 months before it can be detected clinically, or that can monitor the success of anti-TB therapy. Further insights can be obtained from studies of BCG vaccination and new TB vaccines. For example, epigenetic changes associated with trained immunity and a stronger immune responses following BCG vaccination can be identified. These omics approaches may be particularly valuable when linked to studies of mycobacterial growth inhibition, as a direct read-out of the ability to control mycobacterial growth. The second generation of omics studies is identifying much smaller signatures based on as few as 3 or 4 genes. Thus, narrowing down omics-derived biosignatures to a manageable set of markers now opens the way to field-friendly point of care assays.

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“…The following day, 10 µl of the compounds at concentrations ranging from 1 to 25 µM were added at the same time or 2 h before the addition of PMA (30 ng/ml). After incubation for 48 h, culture supernatants were obtained for ELISA, and the cells obtained for immuno-fluorescent or western blot analysis following centrifugation (4,000 rpm, 3 min) as previously described [15].…”

Section: Effect Of Compounds On Pma-stimulated Thp-1 Cellsmentioning

confidence: 99%

“…It is also known that other enzymes such as matrix metalloproteinases (MMPs) can cleave OPN at non-thrombin cleavage sites [13,14]. Accumulation of α4β1 and other integrin-bearing cells is reported in MTB infection [15]. Recently, we showed that small amounts of FL-OPN and tr-OPN were detected in the supernatants of non-phorbol 12-myristate 13-acetate (PMA)-stimulated cells by ELISA, with increased levels of all forms, including undefined Ud-OPN, in PMA-stimulated cells [16].…”

mentioning

confidence: 99%

Inhibition of Osteopontin Synthesis in THP-1 Cells Stimulated with Phorbol 12-Myristate 13-Acetate by Brefelamide Derivatives

Bai¹,

Matsuba²,

Kikuchi³

et al. 2019

Preprint

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Plasma osteopontin (OPN) levels are elevated in mycobacterium tuberculosis patients and may involve granuloma formation. New inhibitors using brefelamide, an aromatic amide isolated from Dictyostelium cellular slim molds which may inhibit OPN transcription at concentration of 1M, were synthesized as compounds C, D and E. Their inhibitory activity against OPN synthesis in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells was confirmed using enzyme-linked immunosorbent assay (ELISA), a multicolor immune-fluorescent microscope and western blot analysis. For the ELISA performed using the full-length OPN, each compound showed significant inhibition. Detailed analysis were done using C and D. They also showed inhibitory activity when used on another ELISA system to detect the immune-related form of OPN and their IC50 were 0.6 and 1.2 M for compounds C and D, respectively. Fluorescent particle count of stained cell numbers by O-17 showed the inhibition. Antibodies for O-17 and 34E3, which recognize OPN N-terminus and thrombin-cleaved site, respectively, detected distinct bands on the western blots following PMA stimulation. The decrease in full-length OPN detected by O-17 in the compound-treated cells was identified via western blot analysis. These newly-developed compounds may therefore be used in clinical trials for cancer and infectious diseases.

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Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4β1–Expressing Immune Cells

Cited by 46 publications

References 45 publications

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

l-Arginine Synthesis from l-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

Addressing diversity in tuberculosis using multidimensional approaches

Inhibition of Osteopontin Synthesis in THP-1 Cells Stimulated with Phorbol 12-Myristate 13-Acetate by Brefelamide Derivatives

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