Capillary Thrombosis as a Cause of Death in Anthrax

Dalldorf, Frederic G.; Beall, Francis A.

doi:10.21236/ad0484326

Cited by 14 publications

(19 citation statements)

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“…Disruption of tight junctions and paracellular traversal between brain endothelial cells is one strategy employed by microbial pathogens to penetrate the BBB (29 (5,9) and endothelial cell dysfunction (60), we sought to determine the contribution of LF and EF to hBMEC barrier integrity during infection by monitoring changes in transendothelial electrical resistance (TEER) across hBMECs and cell monolayer integrity (reactance) in real time by ECIS (Applied BioPhysics, Troy, NY). As described in Materials and Methods, hBMEC monolayers were seeded on electrode arrays until a stable resistance of 800 ⍀ was reached.…”

Section: Resultsmentioning

confidence: 99%

Contribution of Lethal Toxin and Edema Toxin to the Pathogenesis of Anthrax Meningitis

et al. 2011

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Bacillus anthracis is a Gram-positive spore-forming bacterium that causes anthrax disease in humans and animals. Systemic infection is characterized by septicemia, toxemia, and meningitis, the main neurological complication associated with high mortality. We have shown previously that B. anthracis Sterne is capable of blood-brain barrier (BBB) penetration, establishing the classic signs of meningitis, and that infection is dependent on the expression of both major anthrax toxins, lethal toxin (LT) and edema toxin (ET). Here we further investigate the contribution of the individual toxins to BBB disruption using isogenic toxin mutants deficient in lethal factor, ⌬LF, and edema factor, ⌬EF. Acute infection with B. anthracis Sterne and the ⌬LF mutant resulted in disruption of human brain microvascular endothelial cell (hBMEC) monolayer integrity and tight junction protein zona occludens-1, while the result for cells infected with the ⌬EF mutant was similar to that for the noninfected control. A significant decrease in bacterial invasion of BBB endothelium in vitro was observed during infection with the ⌬LF strain, suggesting a prominent role for LT in promoting BBB interaction. Further, treatment of hBMECs with purified LT or chemicals that mimic LT action on host signaling pathways rescued the hypoinvasive phenotype of the ⌬LF mutant and resulted in increased bacterial uptake. We also observed that toxin expression reduced bacterial intracellular survival by inducing the bulk degradative autophagy pathway in host cells. Finally, in a murine model of anthrax meningitis, mice infected with the ⌬LF mutant exhibited no mortality, brain bacterial load, or evidence of meningitis compared to mice infected with the parental or ⌬EF strains.

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Section: Resultsmentioning

confidence: 99%

Contribution of Lethal Toxin and Edema Toxin to the Pathogenesis of Anthrax Meningitis

et al. 2011

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“…Vascular dysfunction and thrombosis have been described in association with anthrax infection in humans (9,60) and animals (60)(61)(62)(63)(64). This type of classic vasculitis induced by endothelial adherence of inflammatory cells and fibrinoid necrosis of vessels did not occur in LT-treated mice, despite similar accumulation of pleural fluid in human anthrax subjects, animal models (2,9,11,14,65,66), and LT-treated mice.…”

Section: Figure 11mentioning

confidence: 99%

“…This type of classic vasculitis induced by endothelial adherence of inflammatory cells and fibrinoid necrosis of vessels did not occur in LT-treated mice, despite similar accumulation of pleural fluid in human anthrax subjects, animal models (2,9,11,14,65,66), and LT-treated mice. LT induction of shock by interference with endothelial cell function has been proposed (2,7,63,64), but no evidence of direct LT effects on endothelium has been presented. If vascular collapse occurs in LT-treated mice, it is quite different from that associated with endotoxic shock.…”

Section: Figure 11mentioning

confidence: 99%

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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“…14 Vascular dysfunction or injury has long been considered a hallmark of anthrax pathogenesis. [15][16][17] Prominent pathological features of systemic anthrax infection include vascular leakage, hemorrhages, and vasculitis. Guarner et al 18 reported progressive and persistent pleural effusions as the main feature in inhalational anthrax patients from the 2001 bioterrorism attack in the United States.…”

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confidence: 99%

Anthrax Lethal Toxin Induces Endothelial Barrier Dysfunction

Warfel

Steele

D’Agnillo

2005

The American Journal of Pathology

145

181

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Hemorrhage and pleural effusion are prominent pathological features of systemic anthrax infection. We examined the effect of anthrax lethal toxin (LT), a major virulence factor of Bacillus anthracis, on the barrier function of primary human lung microvascular endothelial cells. We also examined the distribution patterns of cytoskeletal actin and vascular endothelial-cadherin (VE-cadherin), both of which are involved in barrier function regulation. Endothelial monolayers cultured on porous membrane inserts were treated with the LT components lethal factor (LF) and protective antigen (PA) individually, or in combination. LT induced a concentration-and timedependent decrease in transendothelial electrical resistance that correlated with increased permeability to fluorescently labeled albumin. LT also produced a marked increase in central actin stress fibers and significantly altered VE-cadherin distribution as revealed by immunofluorescence microscopy and cell surface enzyme-linked immunosorbent assay. Bacillus anthracis, the causative agent of anthrax, is a spore-forming gram-positive bacterium. Anthrax toxin, the major virulence factor of B. anthracis, is composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA and LF combine to form lethal toxin (LT), and EF combines with PA to form edema toxin (ET).1-3 PA binds at least two identified cell surface receptors, tumor endothelial marker 8 and capillary morphogenesis protein 2.2,4,5 Once formed, PA-receptor complexes facilitate the endocytosis of LF and EF. Inside cells, LF acts as a metalloprotease that cleaves all of the mitogen activated protein kinase kinases (MEKs) except MEK 5, thus disrupting the activation of major mitogenactivated protein kinases (MAPKs): extracellular signalregulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun NH 2 -terminal kinases (JNK).6 -8 EF acts as a Ca 2ϩ / calmodulin-dependent adenylate cyclase that causes a dramatic increase in intracellular levels of cAMP.9,10 Evidence to date suggests that LT may play a more significant role than ET in the pathogenesis of systemic anthrax. In several animal models, intravascular injections of purified LT are lethal. [11][12][13] In addition, attenuated B. anthracis strains unable to produce functional LF are 1000-fold less virulent than normal strains, whereas EFlacking strains are 10-fold less virulent.

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Capillary Thrombosis as a Cause of Death in Anthrax

Cited by 14 publications

References 1 publication

Contribution of Lethal Toxin and Edema Toxin to the Pathogenesis of Anthrax Meningitis

Contribution of Lethal Toxin and Edema Toxin to the Pathogenesis of Anthrax Meningitis

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

Anthrax Lethal Toxin Induces Endothelial Barrier Dysfunction

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