Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Stearns-Kurosawa, Deborah J.; Lupu, Florea; Taylor, Fletcher B.; Kinasewitz, Gary T.; Kurosawa, Shinichiro

doi:10.2353/ajpath.2006.051330

Cited by 91 publications

(107 citation statements)

References 65 publications

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“…26,28 Consequently, elicitation of circulating D-dimer and TAT suggests an induction of coagulation activation or disseminated intravascular coagulation (DIC). 26,28 To investigate role of LT on the induction of DIC, which was reported in B. anthracis-challenged animals, [29][30][31] we analyzed the plasma levels of D-dimer and TAT complex ( Fig. 2A, B).…”

Section: Lt Treatments Prolong Plasma Clottingmentioning

confidence: 99%

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Sun¹,

Lee

Kau

et al. 2015

Virulence

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(2015) Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice, Virulence, 6:5, 466-475, DOI: 10.1080/21505594.2015 Keywords: Anthrax, coagulation factor VIII, hemorrhage, lethal toxinMice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-offunction approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax.

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Section: Lt Treatments Prolong Plasma Clottingmentioning

confidence: 99%

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Sun¹,

Lee

Kau

et al. 2015

Virulence

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“…injection of anthrax toxin proteins (1)(2)(3)(4)(5)(6)(7)(8). The importance of blood vessels and endothelial cells in anthrax toxicity has been difficult to investigate because of the inability to observe progressive vascular changes without sacrificing the mammalian host.…”

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confidence: 99%

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Bolcome

Sullivan

Zeller

et al. 2008

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

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Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/ vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.endothelial ͉ vascular permeability ͉ VEGF

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“…In this report we extended analyses of these proteases to cleavage of VWF and its natural regulator ADAMTS13. The choice of these proteins was determined by their important roles in hemostasis along with the observations on severe DIC-like coagulopathy in anthrax infection (6,8,45). For example, VWF-deficient mice develop spontaneous bleeding in intra-abdomen and massive hemorrhage in the neck and head (46).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical manifestations range from asymptomatic compensated DIC to shock and death. In the nonhuman primate model the infection with a toxigenic B. anthracis Sterne 34F 2 also results in changes of vascular permeability, DIC, and systemic inflammation (8).…”

mentioning

confidence: 99%

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

Chung

Popova

Jorgensen

et al. 2008

Journal of Biological Chemistry

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Pathology data from the anthrax animal models show evidence of significant increases in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and aggressive disseminated intravascular coagulation. In this study we hypothesized that anthrax infection modulates the activity of von Willebrand factor (VWF) and its endogenous regulator ADAMTS13, which play important roles in hemostasis and thrombosis, including interaction of endothelial cells with platelets. We previously demonstrated that purified anthrax neutral metalloproteases Npr599 and InhA are capable of cleaving a variety of host structural and regulatory proteins. Incubation of human plasma with these proteases at 37°C in the presence of urea as a mild denaturant results in proteolysis of VWF. Also in these conditions, InhA directly cleaves plasma ADAMTS13 protein. Npr599 and InhA digest synthetic VWF substrate FRETS-VWF73. Amino acid sequencing of VWF fragments produced by InhA suggests that one of the cleavage sites of VWF is located at domain A2, the target domain of ADAMTS13. Proteolysis of VWF by InhA impairs its collagen binding activity (VWF:CBA) and ristocetin-induced platelet aggregation activity. In plasma from anthrax spore-challenged DBA/2 mice, VWF antigen levels increase up to 2-fold at day 3 post-infection with toxigenic Sterne 34F 2 strain, whereas VWF:CBA levels drop in a time-dependent manner, suggesting dysfunction of VWF instead of its quantitative deficiency. This conclusion is further supported by significant reduction in the amount of VWF circulating in blood in the ultra-large forms. In addition, Western blot analysis shows proteolytic depletion of ADAMTS13 from plasma of spore-challenged mice despite its increased expression in the liver. Our results suggest a new mechanism of anthrax coagulopathy affecting the levels and functional activities of both VWF and its natural regulator ADAMTS13. This mechanism may contribute to hemorrhage and thrombosis typical in anthrax.Bacillus anthracis, the causative agent of anthrax, is a zoonotic, Gram-positive, spore-forming Bacillus. It is capable of causing a highly lethal systemic infection in people and experimental animals upon inhalation of the spores. The pathological mechanisms underlying high mortality of inhalation anthrax infection are complex and remain insufficiently understood. The major virulence factors, lethal toxin (LT) 2 and edema toxin (ET) produced by B. anthracis can cause death of experimental animals with symptoms resembling those of anthrax infection. Therefore, many studies have been focused on the cytotoxic effects of LT, including the cells of monocyte lineage (peripheral blood monocytes, macrophages, and dendritic cells) (1) and epithelial cells (2). It has also been reported that the LT-induced cell death could cause a massive release of the pro-inflammatory cytokines, such as the tumor necrosis factor ␣ (TNF␣), which may result in lethality (3), but recent data clearly indicate that the intoxication mediate...

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Sepsis and Pathophysiology of Anthrax in a Nonhuman Primate Model

Cited by 91 publications

References 65 publications

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

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