TNF Receptor 1, IL-1 Receptor, and iNOS Genetic Knockout Mice Are Not Protected from Anthrax Infection

Kalns, John; Scruggs, Julie; Millenbaugh, Nancy J.; Vivekananda, Jeeva; Shealy, David J.; Eggers, Jeffrey S.; Kiel, Johnathan L.

doi:10.1006/bbrc.2002.6626

Cited by 36 publications

(34 citation statements)

References 17 publications

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“…Despite harboring toxin-sensitive and resistant macrophages, both strains are susceptible to anthrax infection (17,25) and, as reported here, to LT. BALB/cJ mice succumb more rapidly, but both strains experience a similar course of disease, with hypoxia-mediated necrosis of liver and metaphyseal bone marrow as hallmarks of crisis, accompanied by pleural effusions. Contrary to previous hypotheses (18), hallmarks of cytokine-induced shock such as inflammation, fibrin clots and associated thrombosis, DIC, neutrophil margination and associated endothelial cell damage, renal dysfunction, and TNF-α production are absent in LT-treated mice.…”

Section: Discussionsupporting

confidence: 63%

Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

Moayeri¹,

Haines²,

Young³

et al. 2003

J. Clin. Invest.

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Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1β. No changes in TNF-α occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-α–independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin

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Section: Discussionsupporting

confidence: 63%

Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

Moayeri¹,

Haines²,

Young³

et al. 2003

J. Clin. Invest.

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“…Nitric oxide production potential is predicted not to impact the response to combination therapy. In agreement with this nonintuitive prediction, and despite studies that suggest a role for iNOS-derived NO in the successful response against anthrax (55, 56), Kalns et al (57) suggested that mice deficient in iNOS are not protected from anthrax infection. Therefore, our simulations points to potential biomarkers to evaluate the potential of a therapeutic response to antibiotics in sick previously vaccinated individuals.…”

Section: Discussionmentioning

confidence: 69%

Comparison of Clinical Manifestations and Outcome of Community-Acquired Bloodstream Infections Among the Oldest Old, Elderly, and Adult Patients

et al. 2007

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Bacillus anthracis (anthrax) can trigger an acute inflammatory response that results in multisystem organ failure and death. Previously, we developed a mathematical model of acute inflammation after gram-negative infection that had been matched qualitatively to literature data. We modified the properties of the invading bacteria in that model to those specific to B. anthracis and simulated the host response to anthrax infection. We simulated treatment strategies against anthrax in a genetically diverse population including the following: (1) antibiotic treatment initiated at various time points, (2) antiprotective antigen vaccine, and (3) a combination of antibiotics and vaccine. In agreement with studies in mice, our simulations showed that antibiotics only improve survival if administered early in the course of anthrax infection. Vaccination that leads to the formation of antibodies to protective antigen is anti-inflammatory and beneficial in averting shock and improving survival. However, antibodies to protective antigen alone are predicted not to be universally protective against anthrax infection. Rather, our simulations suggest that an optimal strategy would require both vaccination and antibiotic administration.

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“…Based on previous studies in which antagonism of IL-1b or use of anti-oxidants protected mice from the lethal effects of LT, Kalns et al [44] delivered LT to mice via infection with live, germinationproficient BA spores. Contrary to their expectation that mice lacking either responsiveness to IL-1b or ability to generate free radicals (i.e.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1b accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1b expression in response to BA spores is required for anti-BA host defenses. Caspase-1 -/-and IL-1b -/-mice are more susceptible than wild-type (WT) mice to lethal BA infection, are less able to kill BA both in vivo and in vitro, and addition of rIL-1b to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1b and nitric oxide, by which BA are killed in WT but not in caspase-1 -/-mice, suggesting that the spore itself stimulated inflammatory responses.While spores induced IL-1b in LT-susceptible and -resistant macrophages, LT induced IL-1b only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1b. While both spores and LT induced caspase-1 activity and IL-1b, LT did not induce IL-1b mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1b by distinct signaling pathways. Whereas the spore-induced IL-1b limits BA infection, LT-induced IL-1b enables BA to escape host defenses.

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TNF Receptor 1, IL-1 Receptor, and iNOS Genetic Knockout Mice Are Not Protected from Anthrax Infection

Cited by 36 publications

References 17 publications

Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

Comparison of Clinical Manifestations and Outcome of Community-Acquired Bloodstream Infections Among the Oldest Old, Elderly, and Adult Patients

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

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