Histopathology in a murine model of anthrax

Duong, Scott; Chiaraviglio, Lucius; Kirby, James E.

doi:10.1111/j.0959-9673.2006.00473.x

Cited by 28 publications

(22 citation statements)

References 33 publications

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“…8D and E). These changes have been documented frequently in animal anthrax models and are considered to be key features of this disease (18,27,64,65) or of intoxication with anthrax toxins alone (23,39). These data suggest that the spores were being retained at the site of injection, germinating, and forming vegetative (toxin-producing) bacilli.…”

Section: Resultsmentioning

confidence: 84%

Role of Purine Biosynthesis in Bacillus anthracis Pathogenesis and Virulence

et al. 2011

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Bacillus anthracis, the etiological agent of anthrax, is a spore-forming, Gram-positive bacterium and a category A biothreat agent. Screening of a library of transposon-mutagenized B. anthracis spores identified a mutant displaying an altered phenotype that harbored a mutated gene encoding the purine biosynthetic enzyme PurH. PurH is a bifunctional protein that catalyzes the final steps in the biosynthesis of the purine IMP. We constructed and characterized defined purH mutants of the virulent B. anthracis Ames strain. The virulence of the purH mutants was assessed in guinea pigs, mice, and rabbits. The spores of the purH mutants were as virulent as wild-type spores in mouse intranasal and rabbit subcutaneous infection models but were partially attenuated in a mouse intraperitoneal model. In contrast, the purH mutant spores were highly attenuated in guinea pigs regardless of the administration route. The reduced virulence in guinea pigs was not due solely to a germination defect, since both bacilli and toxins were detected in vivo, suggesting that the significant attenuation was associated with a growth defect in vivo. We hypothesize that an intact purine biosynthetic pathway is required for the virulence of B. anthracis in guinea pigs.

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Section: Resultsmentioning

confidence: 84%

Role of Purine Biosynthesis in Bacillus anthracis Pathogenesis and Virulence

et al. 2011

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“…The fine mechanisms of bacterial regulation are thus likely able to operate in the tissue environment that varies in a complex temporal way through the crosstalk between the bacteria and the host control mechanisms. The model system we describe here is therefore complementary to experimental models described in previous studies, using systemic injection of purified ET or LT, 16,17 or infection with nonencapsulated 9,18 or with an encapsulated laboratory B. anthracis. 20,21 These experimental models preferentially explored the long-distance effects of significant amounts of circulating toxins, thus mimicking the terminal stage of anthrax.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Dumetz

Jouvion

Khun

et al. 2011

The American Journal of Pathology

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Powerful noninvasive imaging technologies enable realtime tracking of pathogen-host interactions in vivo, giving access to previously elusive events. We visualized the interactions between wild-type Bacillus anthracis and its host during a spore infection through bioluminescence imaging coupled with histology. We show that edema toxin plays a central role in virulence in guinea pigs and during inhalational infection in mice. Edema toxin (ET), but not lethal toxin (LT), markedly modified the patterns of bacterial dissemination leading, to apparent direct dissemination to the spleen and provoking apoptosis of lymphoid cells. Each toxin alone provoked particular histological lesions in the spleen. When ET and LT are produced together during infection, a specific temporal pattern of lesion developed, with early lesions typical of LT, followed at a later stage by lesions typical of ET. Our study provides new insights into the complex spatial and temporal effects of B. anthracis toxins in the infected host, suggesting a greater role than previously suspected for ET in anthrax and suggesting that therapeutic targeting of ET contributes to protection.

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“…B. anthracis is a spore-forming bacterium that is the etiological agent of anthrax and a weapon of bioterrorism (13,14). Upon exposure to the host, spores are engulfed by local macrophages, where they germinate into vegetative cells and replicate as the macrophages travel to lymph nodes (15)(16)(17)(18). Vegetative bacilli then escape the cell and produce key virulence factors that contribute to the manifestation of disease.…”

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confidence: 99%

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

2015

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bWhereas DNA provides the information to design life and proteins provide the materials to construct it, the metabolome can be viewed as the physiology that powers it. As such, metabolomics, the field charged with the study of the dynamic small-molecule fluctuations that occur in response to changing biology, is now being used to study the basis of disease. Here, we describe a comprehensive metabolomic analysis of a systemic bacterial infection using Bacillus anthracis, the etiological agent of anthrax disease, as the model pathogen. An organ and blood analysis identified approximately 400 metabolites, including several key classes of lipids involved in inflammation, as being suppressed by B. anthracis. Metabolite changes were detected as early as 1 day postinfection, well before the onset of disease or the spread of bacteria to organs, which testifies to the sensitivity of this methodology. Functional studies using pharmacologic inhibition of host phospholipases support the idea of a role of these key enzymes and lipid mediators in host survival during anthrax disease. Finally, the results are integrated to provide a comprehensive picture of how B. anthracis alters host physiology. Collectively, the results of this study provide a blueprint for using metabolomics as a platform to identify and study novel host-pathogen interactions that shape the outcome of an infection. Metabolomics, a quickly emerging "omics" field in systems biology, is the global analysis of small molecules in a biological sample (1). Since the 1950s, the central dogma of biological information has been the transition from genes to transcript to protein (2). Only recently has the use of high-throughput systems biology been used to study the products of protein activity, the metabolites. The metabolome represents all endogenous and exogenous low-molecular-mass (Ͻ1-kDa) molecules present in a biological state, providing an instantaneous "snapshot" of the cell's metabolic and physiological activity (3). Applications of global metabolomic analysis fall into three broad categories: (i) disease diagnosis, (ii) biomarker and drug discovery, and (iii) study of metabolic pathways and their perturbations due to external factors (1). The analysis of altered metabolites has the potential for discovery of new biomarkers, thus providing the possibility of earlier intervention and insights into the mechanisms of diseases (4).The diagnosis of a bacterial infection encompasses an assessment of clinical symptoms, positive culture of an organism from tissues or blood, and/or reliance on often expensive, outsourced molecular methods (5). Metabolomics provides a unique perspective on bacterial infections as it is able to comprehensively characterize a vast number of metabolic changes in response to a biological perturbation within the host (2). In addition to the potential for biomarker discovery, the metabolic profiles obtained from this analysis can give insight into the identity and nature of molecules involved in the immune response, detect alterations in ho...

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Histopathology in a murine model of anthrax

Cited by 28 publications

References 33 publications

Role of Purine Biosynthesis in Bacillus anthracis Pathogenesis and Virulence

Role of Purine Biosynthesis in Bacillus anthracis Pathogenesis and Virulence

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

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