Susceptibility to Anthrax Lethal Toxin-Induced Rat Death Is Controlled by a Single Chromosome 10 Locus That Includes rNlrp1

Newman, Zachary L.; Printz, Morton P.; Liu, Shihui; Crown, Devorah; Breen, Laura; Miller-Randolph, Sharmina; Flodman, Pamela; Leppla, Stephen H.; Moayeri, Mahtab

doi:10.1371/journal.ppat.1000906

Cited by 87 publications

(137 citation statements)

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“…However, the results from the experiment comparing lethal toxin in SpragueDawley and Lewis hearts (experiment 7) do not support such a relationship. Sensitivity to lethal toxin-induced death in rats has been mapped to a single locus, rNlrp1 (23). While variations in this genetic locus conferred differing survival benefits with lethal toxin in vivo, in experiment 7 rNlrp1 did not appear to differentially influence myocardial function.…”

Section: Discussionmentioning

confidence: 99%

“…To examine whether the resistance to the lethal effects of lethal toxin observed in vivo in Lewis rats (23) was reproducible in an isolated heart model, hearts from SpragueDawley and Lewis rats were perfused in a nonrecirculating model Values are means Ϯ SE. *Controls included animals receiving diluents of edema toxin or PA alone.…”

Section: Study Designsmentioning

confidence: 99%

“…The lethal factor protein used had the non-native HMAGG NH 2-terminal sequence. This preparation of toxin was used in prior experiments investigating the strain sensitivity of rats to the lethal effects of lethal toxin (23). The preparation, when infused over 24 h in the Sprague-Dawley rat, has also been shown to produce hypotension similar to that occurring with lethal toxin prepared from E. coli (6,8).…”

Section: Toxin and Treatmentsmentioning

confidence: 99%

“…Effluent and myocardial cAMP levels were measured during edema toxin perfusion. Finally, we compared the effects of lethal toxin in two strains of rats previously shown to either be sensitive (Sprague-Dawley) or resistant (Lewis) to this toxin's lethal effects (23).…”

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Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

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Okugawa

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Eichacker PQ. Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model. Am J Physiol Heart Circ Physiol 300: H1108 -H1118, 2011. First published January 7, 2011; doi:10.1152/ajpheart.01128.2010.-While anthrax edema toxin produces pronounced tachycardia and lethal toxin depresses left ventricular (LV) ejection fraction in in vivo models, whether these changes reflect direct cardiac effects as opposed to indirect ones related to preload or afterload alterations is unclear. In the present study, the effects of edema toxin and lethal toxin were investigated in a constant pressure isolated perfused rat heart model. Compared with control hearts, edema toxin at doses comparable to or less than a dose that produced an 80% lethality rate (LD 80) in vivo in rats (200, 100, and 50 ng/ml) produced rapid increases in heart rate (HR), coronary flow (CF), LV developed pressure (LVDP), dP/dt max, and rate-pressure product (RPP) that were most pronounced and persisted with the lowest dose (P Յ 0.003). Edema toxin (50 ng/ml) increased effluent and myocardial cAMP levels (P Յ 0.002). Compared with dobutamine, edema toxin produced similar myocardial changes, but these occurred more slowly and persisted longer. Increases in HR, CF, and cAMP with edema toxin were inhibited by a monoclonal antibody blocking toxin uptake and by adefovir, which inhibits the toxin's intracellular adenyl cyclase activity (P Յ 0.05). Lethal toxin at an LD 80 dose (50 ng/ml) had no significant effect on heart function but a much higher dose (500 ng/ml) reduced all parameters (P Յ 0.05). In conclusion, edema toxin produced cAMP-mediated myocardial chronotropic, inotropic, and vasodilatory effects. Vasodilation systemically with edema toxin could contribute to shock during anthrax while masking potential inotropic effects. Although lethal toxin produced myocardial depression, this only occurred at high doses, and its relevance to in vivo findings is unclear.heart function MORTALITY WITH SHOCK during the 2001 United States anthrax outbreak was high despite aggressive support (15). The risk of anthrax persists, as evidenced by recent cases of highly fatal soft tissue infections in the United Kingdom (2). Bacillus anthracis produces two toxins: lethal toxin, made up of protective antigen and lethal factor, and edema toxin, made up of protective antigen and edema factor (18, 21,28,38). Protective antigen mediates the cellular uptake of the two toxigenic components, lethal and edema factors. Lethal factor is a zinc metalloprotease that inactivates MAPK kinases (18). Edema factor has highly active calmodulin-dependent adenyl cyclase activity that acts to perturb PKA-dependent signaling (21, 25). While lethal toxin and edema toxin are associated with the development of shock during anthrax, the mechanisms underlying these effects remain unclear (28).One group (36, 37) has shown that rapid edema toxin administration in rats produces hypotension and tachycardia and reduced left...

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Section: Discussionmentioning

confidence: 99%

Section: Study Designsmentioning

confidence: 99%

Section: Toxin and Treatmentsmentioning

confidence: 99%

mentioning

confidence: 99%

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Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Hicks

Okugawa

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…There are two NLRP1 paralogs in rats (Nlrp1a and Nlrp1b) (24): the Nlrp1a paralog is associated with rat macrophage susceptibility to LeTx (25), but little is known about the Nlrp1b paralog. Amino-terminal cleavage of murine NLRP1B or rat NLRP1A in response to Toxoplasma gondii has not been demonstrated, and it might be that the mechanism of activation is distinct from that of LeTx.…”

Section: Discussionmentioning

confidence: 99%

Distinct Regions of NLRP1B Are Required To Respond to Anthrax Lethal Toxin and Metabolic Inhibition

2014

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Pattern recognition receptors monitor for signs of infection or cellular dysfunction and respond to these events by initiating an immune response. NLRP1B is a receptor that upon activation recruits multiple copies of procaspase-1, which promotes cytokine processing and a proinflammatory form of cell death termed pyroptosis. NLRP1B detects anthrax lethal toxin when the toxin cleaves an amino-terminal fragment from the protein. In addition, NLRP1B is activated when cells are deprived of glucose or treated with metabolic inhibitors, but the mechanism by which the resulting reduction in cytosolic ATP is sensed by NLRP1B is unknown. Here, we addressed whether these two activating signals of NLRP1B converge on a common sensing system. We show that an NLRP1B mutant lacking the amino-terminal region exhibits some spontaneous activity and fails to be further activated by lethal toxin. This mutant was still activated in cells depleted of ATP, however, indicating that the amino-terminal region is not the sole sensing domain of NLRP1B. Mutagenesis of the leucine-rich repeat domain of NLRP1B provided evidence that this domain is involved in autoinhibition of the receptor, but none of the mutants tested was specifically defective at sensing activating signals. Comparison of two alleles of NLRP1B that differed in their response to metabolic inhibitors, but not to lethal toxin, led to the finding that a repeated sequence in the function to find domain (FIIND) that arose from exon duplication facilitated detection of ATP depletion. These results suggest that distinct regions of NLRP1B detect activating signals.

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Exceptionally Selective Substrate Targeting by the Metalloprotease Anthrax Lethal Factor

Turk

2018

Protein Reviews – Purinergic Receptors

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Susceptibility to Anthrax Lethal Toxin-Induced Rat Death Is Controlled by a Single Chromosome 10 Locus That Includes rNlrp1

Cited by 87 publications

References 41 publications

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Distinct Regions of NLRP1B Are Required To Respond to Anthrax Lethal Toxin and Metabolic Inhibition

Exceptionally Selective Substrate Targeting by the Metalloprotease Anthrax Lethal Factor

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