The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax

Coggeshall, K. Mark; Lupu, Florea; Ballard, Jimmy D.; Metcalf, Jordan P.; James, Judith A.; Farris, Darise; Kurosawa, Shinichiro

doi:10.1111/jcmm.12075

Cited by 40 publications

(38 citation statements)

References 70 publications

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“…53,54 The drug rFVIII may enable enhancing coagulation in patients with anthrax who exhibit severe hemorrhage and coagulopathy, as described in clinical settings. [9][10][11][12]31 To develop an effective treatment against anthrax, combining other anti-anthrax agents with a coagulation intervention strategy may be a feasible approach. Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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: Discussionmentioning

confidence: 99%

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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“…In support of the previous finding, genetic deletion of the exotoxin receptors on immune cells, cardiac cells and smooth muscle cells protect mice from toxemia [128]. In contrast to the toxemia mediated death model, others have argued that the exotoxin merely enables the bacilli to reach a high bacterial burden, which in turn triggers sepsis [95,126]. Pathological examination of animals that died from injected exotoxin did not show evidence of fibrin deposits, vasculitis, inflammation, or pleural effusions that are often seen at end stages of anthrax [129,131].…”

Section: Death Of the Hostsupporting

confidence: 51%

“…While figures vary depending on the animal model, the terminal blood colony forming units (CFU) counts tend to vary between 10 4 -10 9 CFU/mL [9]. However, there is debate as to whether toxemia or sepsis due to bacteremia is the cause of death in the animal [126][127][128][129]. B. anthracis infections lead to high levels of the exotoxin being produced in the host, in one case 100µg/mL of protective antigen, a component of the exotoxin, have been detected after death [130].…”

Section: Death Of the Hostmentioning

confidence: 99%

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Lowe

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Bacillus anthracis is a Gram positive sporulating bacterium that is the causative agent of anthrax. Early steps in dissemination are understudied due to the asymptomatic and asynchronous nature of B. anthracis infections. The goals of these studies are to establish a model of the early steps of B. anthracis infections and examine how the initial site of infection and exotoxin production affect bacterial dissemination. In these studies, a mouse model was used in combination with a bioluminescent signature tagged library to determine how B.anthracis disseminates through the host and the roles of an exotoxin component, lethal factor, in colonization and dissemination. This library allowed for real time observation of dissemination and analysis of bacterial population dynamics. In the first set of experiments, mice were infected via inhalational or subcutaneous routes with the tagged library to determine how the bacterial population changed during dissemination. In inhalational and subcutaneous infections, the disseminated population was comprised of a small subset of the original library.This indicated the presence of a population bottleneck, a random decrease in genetic diversity during the infection. Surprisingly, the diminishment and location of the bottleneck varied depending on the initial site of infection. This suggested B. anthracis exploits multiple host environments and some sites may be more permissive for dissemination than others. In the second set of experiments, mice were infected with a signature tagged library where a portion of clones lacked lethal factor. Lethal factor is known to be an important virulence factor as deletion results in attenuated or complete loss of virulence in most animal models. Host survival increased when < 10% of the library produced lethal factor, but few other differences were observed. Furthermore, decreases in the proportion of lethal factor producing clones led to fewer clones disseminating. These findings suggest that a threshold of lethal factor must be ii produced for colonization and dissemination to occur in vivo. In total, this work provides an understanding of how B. anthracis is able to rapidly disseminate from a several tissues and gives insights in where future therapeutics should be focused to reduce disease incidence.iii

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“…PBS controls were culled when the clinical score reached threshold levels as the animals were then close to death (13). Tissues were weighed and homogenized in sterile water, the homogenates were serially diluted in sterile water and plated onto Trypticase soy agar, and the plates were incubated at 37°C for 16 to 24 h. death occurs from overwhelming bacteremia and sepsis due to uncontrolled bacterial proliferation and release of proinflammatory mediators (25). Thus, a therapeutic window may be available if treatment is initiated before extensive bacterial division occurs in the blood.…”

Section: Fig 3 Bmentioning

confidence: 99%

Parenteral Administration of Capsule Depolymerase EnvD Prevents Lethal Inhalation Anthrax Infection

Negus

Vipond

Hatch

et al. 2015

Antimicrob Agents Chemother

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Left untreated, inhalation anthrax is usually fatal. Vegetative forms of Bacillus anthracis survive in blood and tissues during infection due to elaboration of a protective poly-␥-D-glutamic acid (PDGA) capsule that permits uncontrolled bacterial growth in vivo, eventually leading to overwhelming bacillosis and death. As a measure to counter threats from multidrug-resistant strains, we are evaluating the prophylactic and therapeutic potential of the PDGA depolymerase EnvD, a stable and potent enzyme which rapidly and selectively removes the capsule from the surface of vegetative cells. Repeated intravenous administration of 10 mg/kg recombinant EnvD (rEnvD) to mice infected with lethal doses of B. anthracis Ames spores by inhalation prevented the emergence of symptoms of anthrax and death; all animals survived the 5-day treatment period, and 70% survived to the end of the 14-day observation period. In contrast to results in sham-treated animals, the lungs and spleen of rEnvD-dosed animals were free of gross pathological changes. We conclude that rEnvD has potential as an agent to prevent the emergence of inhalation anthrax in infected animals and is likely to be effective against drug-resistant forms of the pathogen.

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The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax

Cited by 40 publications

References 70 publications

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Acquired coagulant factor VIII deficiency induced byBacillus anthracislethal toxin in mice

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Parenteral Administration of Capsule Depolymerase EnvD Prevents Lethal Inhalation Anthrax Infection

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