Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis

Harrison, David E.; Astle, Clinton M.; Niazi, M. Khalid Khan; Major, Samuel; Beamer, Gillian

doi:10.1186/s12979-014-0024-6

Cited by 26 publications

(29 citation statements)

References 31 publications

(37 reference statements)

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“…Over the past few decades, there have been many studies on aging that were associated with high rates of infectious diseases (Yoshikawa, 2000;Gavazzi & Krause, 2002;Gavazzi et al, 2004). It is well known that elderly people are more susceptible to diverse pathogens such as Streptococcus pneumoniae (Meyer, 2005), Mycobacterium tuberculosis (Harrison et al, 2014), Staphylococcus aureus (Kang et al, 2011), and Escherichia coli (Tal et al, 2005) at various sites of infection including the respiratory tract, skin and soft tissue, and the urinary tract.…”

Section: Introductionmentioning

confidence: 99%

Caveolin‐1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection

Ahn

Cho

Song

et al. 2016

Molecular Oral Microbiology

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It is well established that aging is associated with increased susceptibility to infectious diseases. Fusobacterium nucleatum is a well-known bacterial species that plays a central bridging role between early and late colonizers in the human oral cavity. Further, the ability of F. nucleatum to invade gingival fibroblasts (GFs) is critical to the development of periodontal diseases. However, the mechanisms underlying the age-related infection of GFs by F. nucleatum remain unknown. We used young (fourth passage) and senescent (22nd passage) GFs to investigate the mechanisms of F. nucleatum infection in aged GFs and first observed increased invasion of F. nucleatum in senescent GFs. We also found that the co-localization of caveolin-1 (Cav-1), a protein marker of aging, with F. nucleatum and the knockdown of Cav-1 in GFs reduced F. nucleatum invasion. Additionally, F. nucleatum infection triggered the production of reactive oxygen species (ROS) through activation of NADPH oxidase in GFs, but senescent GFs exhibited significantly lower levels of NADPH oxidase activity and ROS production compared with young GFs in both the uninfected and infected conditions. Also, senescent GFs exhibited a decline in proinflammatory cytokine production and extracellular signal regulated kinase (ERK) phosphorylation following F. nucleatum infection. Interestingly, the knockdown of Cav-1 in senescent GFs increased NADPH oxidase activity and caused the upregulation of interleukin-6 and interleukin-8 and the phosphorylation of ERK. Collectively, the increased expression of Cav-1 might play a critical role in F. nucleatum invasion and could hinder the host response in senescent GFs.

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Section: Introductionmentioning

confidence: 99%

Caveolin‐1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection

Ahn

Cho

Song

et al. 2016

Molecular Oral Microbiology

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“…These findings may also suggest that outbred mice are more resistant to olfactory nerve infection than inbred mice. Outbred mice are well known to exhibit stronger resistance to infections, to be more "immunocompetent" and to better reflect immune responses in humans than inbred mice [57][58][59][60][61][62][63][64][65]. Differences in the response to B. pseudomallei infection has also been demonstrated between different inbred mouse strains.…”

Section: Discussionmentioning

confidence: 99%

Burkholderia pseudomallei invades the olfactory nerve and bulb after epithelial injury in mice and causes the formation of multinucleated giant glial cells in vitro

et al. 2020

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The infectious disease melioidosis is caused by the bacterium Burkholderia pseudomallei. Melioidosis is characterised by high mortality and morbidity and can involve the central nervous system (CNS). We have previously discovered that B. pseudomallei can infect the CNS via the olfactory and trigeminal nerves in mice. We have shown that the nerve path is dependent on mouse strain, with outbred mice showing resistance to olfactory nerve infection. Damage to the nasal epithelium by environmental factors is common, and we hypothesised that injury to the olfactory epithelium may increase the vulnerability of the olfactory nerve to microbial insult. We therefore investigated this, using outbred mice that were intranasally inoculated with B. pseudomallei, with or without methimazole-induced injury to the olfactory neuroepithelium. Methimazole-mediated injury resulted in increased B. pseudomallei invasion of the olfactory epithelium, and only in pre-injured animals were bacteria found in the olfactory nerve and bulb. In vitro assays demonstrated that B. pseudomallei readily infected glial cells isolated from the olfactory and trigeminal nerves (olfactory ensheathing cells and trigeminal Schwann cells, respectively). Bacteria were degraded by some cells but persisted in other cells, which led to the formation of multinucleated giant cells (MNGCs), with olfactory ensheathing cells less likely to form MNGCs than Schwann cells. Double Cap mutant bacteria, lacking the protein BimA, did not form MNGCs. These data suggest that injuries to the olfactory epithelium expose the primary olfactory nervous system to bacterial invasion, which can then result in CNS infection with potential pathogenic consequences for the glial cells.PLOS Neglected Tropical Diseases | https://doi.Infections of the central nervous system (CNS), though uncommon, are associated with severe morbidity and mortality. Burkholderia pseudomallei, the causative agent of melioidosis, can infect the CNS. We have shown that B. pseudomallei can enter the CNS via peripheral nerves extending between the nasal cavity and the brain (bypassing the bloodbrain/blood-cerebrospinal fluid barriers). In the current study, we show that prior injury to the olfactory epithelium can increase B. pseudomallei invasion of the olfactory nerve and bulb, highlighting a novel risk factor for CNS infections. We also demonstrate the ability of peripheral nerve glia to internalise B. pseudomallei, resulting in the formation of multinucleated giant cells (MNGCs), dependent on the bacterial protein BimA. These findings provide important new insights into the pathogenesis of B. pseudomallei.B. pseudomallei infects olfactory bulb after injury PLOS Neglected Tropical Diseases | https://doi.

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“…Female 8-week old DO mice from The Jackson Laboratory (Bar harbor, ME, USA) were housed in the Biosafety Levels 3 facility at the New England Regional Biosafety Laboratory (Tufts University, Cummings School of Veterinary Medicine, North Grafton, MA, USA). Mice were infected with 20 to 100 Colony Forming Units of M. tuberculosis Erdman using a CH Technologies nose-only exposure system, as previously described [11][12][13].…”

Section: Tuberculosis Infection Of Diversity Outbred Mice Lung Timentioning

confidence: 99%

“…Agreement of cell-poor necrosis between 2D-TB and the pathologist were determined by many methods: Sensitivity, Specificity, Positive Prediction Value, Dice similarity measurement and Spearman correlation for area (µm). For Dice similarity [13], necrotic areas detected by 2D-TB were marked on whole slide images. An expert pathologist (GB) then classified the marked areas into four categories: 'Agree', 'Mostly Agree', 'Disagree' and 'Uncertain', 'Agree' or 'Mostly Agree' were recorded as True Positive (TP).…”

Section: Measures Of Accuracy To Assess 2d-tb Performancementioning

confidence: 99%

“…Infection incites complex host responses involving epithelial cells, dendritic cells, monocytes, macrophages, myeloid-derived suppressor cells, neutrophils, antigen-independent and antigen-specific lymphocytes, plasma cells, stem cells, stromal cells, and many effector molecules [2][3][4][5][6][7][8]. Cells recruited to the lungs form multiple lesion types, including diffuse lipid pneumonia, bronchiolar obstruction, and granulomas in humans and in experimental animal models [9][10][11][12][13][14][15][16][17]. These different lesions have different functions and outcomes for bacilli and lung tissue [18,19] although detailed structure-function relationships at the cell, molecule, and gene levels remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Automatic Detection of Granuloma Necrosis in Pulmonary Tuberculosis Using a Two-Phase Algorithm: 2D-TB

Kus¹,

Gürcan

Beamer

2019

Microorganisms

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Granuloma necrosis occurs in hosts susceptible to pathogenic mycobacteria and is a diagnostic visual feature of pulmonary tuberculosis (TB) in humans and in super-susceptible Diversity Outbred (DO) mice infected with Mycobacterium tuberculosis. Currently, no published automated algorithms can detect granuloma necrosis in pulmonary TB. However, such a method could reduce variability, and transform visual patterns into quantitative data for statistical and machine learning analyses. Here, we used histopathological images from super-susceptible DO mice to train, validate, and performance test an algorithm to detect regions of cell-poor necrosis. The algorithm, named 2D-TB, works on 2-dimensional histopathological images in 2 phases. In phase 1, granulomas are detected following background elimination. In phase 2, 2D-TB searches within granulomas for regions of cell-poor necrosis. We used 8 lung sections from 8 different super-susceptible DO mice for training and 10-fold cross validation. We used 13 new lung sections from 10 different super-susceptible DO mice for performance testing. 2D-TB reached 100.0% sensitivity and 91.8% positive prediction value. Compared to an expert pathologist, agreement was 95.5% and there was a statistically significant positive correlation for area detected by 2D-TB and the pathologist. These results show the development, validation, and accurate performance of 2D-TB to detect granuloma necrosis.

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Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis

Cited by 26 publications

References 31 publications

Caveolin‐1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection

Caveolin‐1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection

Burkholderia pseudomallei invades the olfactory nerve and bulb after epithelial injury in mice and causes the formation of multinucleated giant glial cells in vitro

Automatic Detection of Granuloma Necrosis in Pulmonary Tuberculosis Using a Two-Phase Algorithm: 2D-TB

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