<i>Bacillus anthracis</i> spores and lethal toxin induce IL‐1β <i>via</i> functionally distinct signaling pathways

Kang, Tae Jin; Basu, Subhendu; Zhang, Lei; Thomas, Karen E.; Vogel, Stefanie N.; Baillie, Les; Cross, Alan S.

doi:10.1002/eji.200838141

Cited by 38 publications

(44 citation statements)

References 47 publications

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“…[43][44][45] Our findings, however, suggest that overstimulation or dysregulation of caspase-1 can also result in disease progression and vascular collapse. It is conceivable that macrophage necrosis results in the release of inflammatory factors that drive disease progression.…”

Section: Conclusion and Therapeutic Potential Of The Studymentioning

confidence: 64%

Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

Muehlbauer

Lima

Goldman

et al. 2010

The American Journal of Pathology

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NOD-like receptors (NLRs) and caspase-1 are critical components of innate immunity, yet their over-activation has been linked to a long list of microbial and inflammatory diseases, including anthrax. The Bacillus anthracis lethal toxin (LT) has been shown to activate the NLR Nalp1b and caspase-1 and to induce many symptoms of the anthrax disease in susceptible murine strains. In this study we tested whether it is possible to prevent LT-mediated disease by pharmacological inhibition of caspase-1. We found that caspase-1 and proteasome inhibitors blocked LT-mediated caspase-1 activation and cytolysis of LT-sensitive (Fischer and Brown-Norway) rat macrophages. The proteasome inhibitor NPI-0052 also prevented disease progression and death in susceptible Fischer rats and increased survival in BALB/c mice after LT challenge. In addition, NPI-0052 blocked rapid disease progression and death in susceptible Fischer rats and BALB/c mice challenged with LT. In contrast, Lewis rats, which harbor LT-resistant macrophages, showed no signs of caspase-1 activation after LT injection and did not exhibit rapid disease progression. Taken together, our findings indicate that caspase-1 activation is critical for rapid disease progression in rodents challenged with LT. Our studies indicate that pharmacological inhibition of NLR signaling and caspase-1 can be used to treat inflammatory diseases.

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Section: Conclusion and Therapeutic Potential Of The Studymentioning

confidence: 64%

Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

Muehlbauer

Lima

Goldman

et al. 2010

The American Journal of Pathology

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“…Antibacterial effects of host endoribonuclease RNase-L (50), interferon-inducible host chemokines (51), and caspase-1-mediated interleukin-1␤ expression (52) have been implicated as important participants in the host defense in mice challenged with Sterne strain of B. anthracis. To date, the role of these critical host targets has not been demonstrated in the highly virulent Ames infection model.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of CD45 Protein-tyrosine Phosphatase Provides Protection against Anthrax Pathogenesis

Panchal

Ulrich

Bradfute

et al. 2009

Journal of Biological Chemistry

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The modulation of cellular processes by small molecule inhibitors, gene inactivation, or targeted knockdown strategies combined with phenotypic screens are powerful approaches to delineate complex cellular pathways and to identify key players involved in disease pathogenesis. Using chemical genetic screening, we tested a library of known phosphatase inhibitors and identified several compounds that protected Bacillus anthracis infected macrophages from cell death. The most potent compound was assayed against a panel of sixteen different phosphatases of which CD45 was found to be most sensitive to inhibition. Testing of a known CD45 inhibitor and antisense phosphorodiamidate morpholino oligomers targeting CD45 also protected B. anthracisinfected macrophages from cell death. However, reduced CD45 expression did not protect anthrax lethal toxin (LT) treated macrophages, suggesting that the pathogen and independently added LT may signal through distinct pathways. Subsequent, in vivo studies with both gene-targeted knockdown of CD45 and genetically engineered mice expressing reduced levels of CD45 resulted in protection of mice after infection with the virulent Ames B. anthracis. Intermediate levels of CD45 expression were critical for the protection, as mice expressing normal levels of CD45 or disrupted CD45 phosphatase activity or no CD45 all succumbed to this pathogen. Mechanism-based studies suggest that the protection provided by reduced CD45 levels results from regulated immune cell homeostasis that may diminish the impact of apoptosis during the infection. To date, this is the first report demonstrating that reduced levels of host phosphatase CD45 modulate anthrax pathogenesis.Interactions between microbes and immune cells play a critical role in microbial pathogenesis. Many pathogenic organisms exploit the host immune machinery and subsequently modulate cell function, signaling, migration, and cytoskeleton rearrangement. Hence, identifying host cellular components with which microbes interact will allow for a more comprehensive understanding of microbial pathogenesis, define common strategies used by multiple pathogens, and elucidate unique tactics evolved by individual species to help establish infections or evade host innate responses. Another interesting aspect of infection is that diverse pathogens seem to target common cellular pathways (1, 2). Thus, identifying host targets exploited by multiple pathogens will be useful in the development of broadspectrum host-oriented therapeutics and vaccines.Protein kinases and phosphatases regulate a range of cellular responses to external and internal stimuli, including cell proliferation, metabolism, and apoptosis. Aberrant kinase and/or phosphatase activities underlie many different types of pathological conditions from cancer to infectious diseases. Protein kinases have been extensively investigated as targets for drug discovery. In addition, phosphatases are now being recognized as important regulators of many biological processes. In particular, there is an inc...

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“…Remarkably, RNase-L Ϫ/Ϫ mice exhibited a dramatic increase in mortality after infection with both bacteria that reflected a compromised immune response and increased bacterial load. Induction of the proinflammatory cytokines, IL-1␤, TNF␣, and IFN␤, which are essential for defense from BA (8) and E. coli (13), was diminished after bacterial infection of RNase-L Ϫ/Ϫ macrophages suggesting that the antibacterial action of RNase-L is mediated, in part, through the regulation of cytokine induction. RNase-L Ϫ/Ϫ mice also displayed a delay in endotoxin-induced lethality, providing further evidence for the physiologic relevance of the impaired cytokine induction phenotype.…”

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confidence: 93%

“…Importantly, the induction of IFN by bacteria is required for the successful resolution of infections by a diverse profile of bacteria, demonstrating its functional role in host defense from bacterial challenge (5)(6)(7). For example, we recently reported a critical role for IFN␤ in the IL-1␤-dependent killing of Bacillus anthracis (BA) spores (8). Thus, a current challenge is to determine the mechanisms by which IFNs exert their antibacterial activity.…”

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confidence: 99%

An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity

Ezelle²,

Kang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Type I IFNs were discovered as the primary antiviral cytokines and are now known to serve critical functions in host defense against bacterial pathogens. Accordingly, established mediators of IFN antiviral activity may mediate previously unrecognized antibacterial functions. RNase-L is the terminal component of an RNA decay pathway that is an important mediator of IFN-induced antiviral activity. Here, we identify a role for RNase-L in the host antibacterial response. RNase-L ؊/؊ mice exhibited a dramatic increase in mortality after challenge with Bacillus anthracis and Escherichia coli; this increased susceptibility was due to a compromised immune response resulting in increased bacterial load. Investigation of the mechanisms of RNase-L antibacterial activity indicated that RNase-L is required for the optimal induction of proinflammatory cytokines that play essential roles in host defense from bacterial pathogens. RNase-L also regulated the expression of the endolysosomal protease, cathepsin-E, and endosome-associated activities, that function to eliminate internalized bacteria and may contribute to RNase-L antimicrobial action. Our results reveal a unique role for RNase-L in the antibacterial response that is mediated through multiple mechanisms. As a regulator of fundamental components of the innate immune response, RNase-L represents a viable therapeutic target to augment host defense against diverse microbial pathogens.cathepsin-E ͉ interferon ͉ 2Ј, 5Ј-oligoadenylate ͉ cytokine ͉ endosome

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Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

Cited by 38 publications

References 47 publications

Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

Reduced Expression of CD45 Protein-tyrosine Phosphatase Provides Protection against Anthrax Pathogenesis

An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity

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