Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice

ABSTRACT: We sought to develop and characterize a novel paucibacillary model in mice, which develop necrotic lung granulomas following infection with Mycobacterium tuberculosis. Paucibacillary infection was established, recapitulating the sterilizing activities of human LTBI regimens. TNF neutralization led to increased lung bacillary load, disrupted granuloma architecture with expanded necrotic foci and reduced tissue hypoxia, and accelerated animal mortality. TNF-neutralized mouse lungs and sera showed significant upregulation of IFN?, IL-1?, IL-6, IL-10, CCL2, CCL3, and matrix metalloproteinase genes Six weeks after aerosol-immunization with recombinant M. bovis BCG overexpressing the 30-kilodalton antigen, C3HeB/FeJ mice were aerosol-infected with M. tuberculosis H37Rv. Six weeks later, mice were treated with one of three standard regimens for latent TB infection (LTBI) or TNF-neutralizing antibody. Mouse lungs were analyzed by histology, positron emission tomography/computed tomography, whole-genome microarrays, and RT-PCR. Lungs and sera were studied by multiplex enzyme-linked immunosorbent assays

ORGANISM(S): Mus musculus

SUBMITTER: Petros Karakousis

PROVIDER: E-GEOD-55183 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:transcriptomic analyses showed there was a very rapid proliferation of Y. pestis in assault on African green monkeys. The bacterial loads were enumerated in the blood at delayed time points supporting earlier observations (Layton et al., 2011). Interpretation of transcriptomic changes reveals that the host defense has been essentially shattered, and the process of multi-organ failure was initiated one day after inhalation exposure. At 24 h post-exposure, the diseased animals were possibly at the middle of their survival curves. Hence, such molecular indicators could have critical therapeutic values, particularly when therapies fail to intervene at the earliest opportunity. In the early phase of pathogenesis, systematic reprogramming of both adaptive and innate immunity programs is mediated, leading to sepsis. Results suggest the possibility of early molecular perturbations in the lungs and muscle tissues, and catabolic related activities, such as biosynthesis. Apoptosis ensued at the early stage, which potentially became rapid by recruiting an increasing number of apoptotic networks. Beyond 24 h, rapid apoptosis could have acted in concert with hypercytokinemia and hyperchemokinemia, resulting in failures of many peripheral organs. Following a published report (Layton et al., 2011), the present study was designed to expose the nonhuman primates with a target dose of 100 Â± 50 ED50 aerosolized Y. pestis strain CO92 under ABSL-3 conditions. Seventy-two hours prior to aerosol exposure, all animals were moved into the ABSL-3 for acclimatization. As described in Figure S1, initial blood draws were carried out 24 h before Y. pestis aerosol challenge. The animals were challenged via aerosol with 1 x 106 virulent organisms while under anesthesia with 4 mg/kg Telazol (Fort Dodge Animal Health, Fort Dodge, IA). Post-exposure clinical illness and disseminated infection were evaluated by direct clinical observations. All animals within each group were exposed on the same day at 30 minute intervals, and subsequent blood draws were conducted at 45 m, 6 h, 9 h, 12 h, 18 h, 24 h, 32 h and 42 h.

Project description:Cigarette smoke (CS) has been reported to increase predisposition to oral cancer and is also recognized as a risk factor for many conditions including periodontal diseases, gingivitis, and other benign mucosal disorders. Smoking cessation remains the most effective approach for minimizing the risk of smoking-related diseases. However, reduction of harmful constituents by heating rather than combusting tobacco, without modifying the amount of nicotine, is a promising new paradigm in harm reduction. In this study, we compared effects of exposure to aerosol derived from a candidate modified risk tobacco product, the tobacco heating system (THS) 2.2, with those of CS generated from the 3R4F reference cigarette. Human organotypic oral epithelial tissue cultures (EpiOral, MatTek Corporation) were exposed for 28 min to 3R4F CS or THS2.2 aerosol, both diluted with air to comparable nicotine concentrations (0.32 or 0.51 mg nicotine/L aerosol/CS for 3R4F and 0.31 or 0.46 mg/L for THS2.2). We also tested one higher concentration (1.09 mg/L) of THS2.2. A systems toxicology approach was employed combining cellular assays (i.e., cytotoxicity and cytochrome P450 activity assays), comprehensive molecular investigations of the buccal epithelial transcriptome (mRNA and miRNA) by means of computational network biology, measurements of secreted proinflammatory markers, and histopathological analysis. We observed that the impact of 3R4F CS was greater than THS2.2 aerosol in terms of cytotoxicity, morphological tissue alterations, and secretion of inflammatory mediators. Analysis of the transcriptomic changes in the exposed oral cultures revealed significant perturbations in various network models such as apoptosis, necroptosis, senescence, xenobiotic metabolism, oxidative stress, and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) signaling. The stress responses following THS2.2 aerosol exposure were markedly decreased, and the exposed cultures recovered more completely compared with those exposed to 3R4F CS.

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Genome-wide characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice

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