Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin

Moayeri, Mahtab; Webster, Jeanette I.; Wiggins, Jason F.; Leppla, Stephen H.; Sternberg, Esther M.

doi:10.1128/iai.73.7.4238-4244.2005

Cited by 37 publications

(42 citation statements)

References 61 publications

(88 reference statements)

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“…In in vitro studies, LeTx inhibited transactivation of dexamethasone-induced GR in both a transfection system and in cells endogenously expressing GR (42). In in vivo studies, LeTx inhibited dexamethasone-induced liver tyrosine aminotransferase activity in BALB/c mice.…”

Section: Potential Mediators and Mechanisms Of Letx-induced Shockmentioning

confidence: 94%

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Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

Sherer

Cui

et al. 2007

Am J Respir Crit Care Med

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Recent research regarding the structure and function of Bacillus anthracis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopeptidase targeting mitogenactivated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response. In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx. Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research.

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Section: Potential Mediators and Mechanisms Of Letx-induced Shockmentioning

confidence: 94%

“…Inhibition of GR function by LeTx raises the possibility that corticosteroid therapy might be beneficial during shock with B. anthracis (42). However, in the limited studies conducted to date, dexamethasone administration was not effective in LeTx-challenged animals models (42).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

Sherer

Cui

et al. 2007

Am J Respir Crit Care Med

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“…For this protocol, intraperitoneal (IP) administration of LF was employed for easy standardization (Kandadi et al, 2012;Moayeri et al, 2003Moayeri et al, , 2005 In terms of duration of the experiment, our approach was based on studies performed earlier. In the light microscopy evaluations here, sinusoidal dilation was seen in tissues of LF-treated rats.…”

Section: Discussionmentioning

confidence: 99%

“…Anthrax LF (recombinant LF from B. anthracis) was purchased from Calbiochem (Merck, Germany, Catalog #176900) and dissolved in sterile distilled water to achieve the concentrations needed for injection(s). This dose was selected based upon studies by Moayeri et al (2005). Twenty-four hours after the injection, a perfusion fixation procedure was performed on all rats by intracardiac administration of neutral formalin while the rats were under Sevorane Õ (Abbott, _ Istanbul, Turkey) anesthesia (inhalation).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Histopathological effects of anthrax lethal factor on rat liver

Altunkaynak

Özbek

2013

Journal of Immunotoxicology

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Bacillus anthracis, the causative agent of anthrax, has become an increasingly important scientific topic due to its potential role in bioterrorism. The lethal toxin (LT) of B. anthracis consists of lethal factor (LF) and a protective antigen (PA). This study investigated whether only lethal factor was efficient as a hepatotoxin in the absence of the PA. To achieve this aim, LF (100 mg/kg body weight, dissolved in sterile distilled water) or distilled water vehicle were intraperitoneally injected once into adult rats. At 24 h post-injection, the hosts were euthanized and their livers removed and tissue samples examined under light and electron microscopes. As a result of LF application, hepatic injury -including cytoplasmic and nuclear damage in hepatocytes, sinusoidal dilatation, and hepatocellular lysis -became apparent. Further, light microscopic analyses of liver sections from the LF-injected rats revealed ballooning degeneration and cytoplasmic loss within hepatocytes, as well as peri-sinusoidal inflammation. Additionally, an increase in the numbers of Kupffer cells was evident. Common vascular injuries were also found in the liver samples; these injuries caused hypoxia and pathological changes. In addition, some cytoplasmic and nuclear changes were detected within the liver ultrastructure. The results of these studies allow one to suggest that LF could be an effective toxicant alone and that PA might act in situ to modify the effect of this agent (or the reverse situation wherein LF modifies effects of PA) such that lethality results.

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“…Nalp1b has been identified as the LeTx macrophage sensitivity locus (Moayeri et al, 2003;Moayeri et al, 2004). The genes involved in regulation of endocrine responses may also be important in LeTx-mediated killing of mice (Moayeri et al, 2005). Though it is only one of the determinants of LeTx-induced lethality of mice, LeTx-induced macrophage death is of significant importance since macrophages are essential for the pathogenesis of B. anthracis.…”

Section: Introductionmentioning

confidence: 99%

AMPD3 is involved in anthrax LeTx-induced macrophage cell death

Lee¹,

Wang²,

Kim³

et al. 2011

Protein Cell

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The responses of macrophages to Bacillus anthracis infection are important for the survival of the host, since macrophages are required for the germination of B. anthracis spores in lymph nodes, and macrophage death exacerbates anthrax lethal toxin (LeTx)-induced organ collapse. To elucidate the mechanism of macrophage cell death induced by LeTx, we performed a genetic screen to search for genes associated with LeTx-induced macrophage cell death. RAW 264.7 cells, a macrophage-like cell line sensitive to LeTx-induced death, were randomly mutated and LeTx-resistant mutant clones were selected. AMP deaminase 3 (AMPD3), an enzyme that converts AMP to IMP, was identified to be mutated in one of the resistant clones. The requirement of AMPD3 in LeTxinduced cell death of RAW 264.7 cells was confirmed by the restoration of LeTx sensitivity with ectopic reconstitution of AMPD3 expression. AMPD3 deficiency does not affect LeTx entering cells and the cleavage of mitogen-activated protein kinase kinase (MKK) by lethal factor inside cells, but does impair an unknown downstream event that is linked to cell death. Our data provides new information regarding LeTx-induced macrophage death and suggests that there is a key regulatory site downstream of or parallel to MKK cleavage that controls the cell death in LeTx-treated macrophages.

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Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin

Cited by 37 publications

References 61 publications

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

Histopathological effects of anthrax lethal factor on rat liver

AMPD3 is involved in anthrax LeTx-induced macrophage cell death

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