Anthrax toxins inhibit immune cell chemotaxis by perturbing chemokine receptor signalling

Paccani, Silvia Rossi; Tonello, Fiorella; Patrussi, Laura; Capitani, Nagaja; Simonato, Morena; Montecucco, Cesare; Baldari, Cosima T.

doi:10.1111/j.1462-5822.2006.00840.x

Cited by 69 publications

(92 citation statements)

References 23 publications

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“…PA combines with LF and EF to form lethal toxin (LT) and edema toxin (ET), respectively (2,8,11,17). Anthrax toxin is believed to be important for outgrowth and trafficking of the bacteria during disease as well as the progression and lethal nature of the disease (2,10,12,19,25,27,36). Because PA is a common component of both ET and LT, most new anthrax vaccines and antibody therapies target PA specifically (9,14).…”

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confidence: 99%

“…The potential use of B. anthracis spores as a biological warfare and bioterror agent has spurred significant efforts toward the development of countermeasures for anthrax (16), including new-generation anthrax vaccines and therapeutics. Most anthrax vaccines and therapeutic antibodies that are currently under development are designed to protect against disease by targeting anthrax toxin, a major virulence factor of B. anthracis that is believed to play a critical role in disease progression (27,36).…”

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confidence: 99%

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Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

Ngundi

Meade

Little

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTAntibodies against the protective antigen (PA) component of anthrax toxin play an important role in protection against disease caused byBacillus anthracis. In this study, we examined defined combinations of PA-specific monoclonal antibodies for their ability to neutralize anthrax toxin in cell culture assays. We observed additive, synergistic, and antagonistic effects of the antibodies depending on the specific antibody combination examined and the specific assay used. Synergistic toxin-neutralizing antibody interactions were examined in more detail. We found that one mechanism that can lead to antibody synergy is the bridging of PA monomers by one antibody, with resultant bivalent binding of the second antibody. These results may aid in optimal design of new vaccines and antibody therapies against anthrax.

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confidence: 99%

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confidence: 99%

Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

Ngundi

Meade

Little

et al. 2012

Clin. Vaccine Immunol.

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“…LT has been shown to inhibit chemotaxis in PBMC's; however, addition of purified LT with ET also leads to an increase in chemotaxis compared to untreated DCs [193,196]. Additionally, recombinant ET is capable of activating glycogen synthase kinase (GSK) in DCs, which in turn is able to fully activate CREB-mediated transcriptional changes shown by Kim et al to be involved with chemotaxis [194,197].…”

Section: Immunological Effectsmentioning

confidence: 99%

“…In vivo clodronate depletion of macrophages sensitizes mice to infection during inhalational anthrax, demonstrating a net protective function of macrophages [191,192]. In vitro treatment of macrophages and peripheral blood lymphocytes with either purified LT or ET reduces phosphorylation of Erk, presumably by independent mechanisms, which lessens chemotaxis toward the chemoattractants SDF-1α and MIP-1α [193]. The reduction is specific for the exotoxins since the MEK inhibitor PD98059 is able to phenocopy the decrease in chemotaxis, supporting a role for Erk1/2 in chemotaxis, and the ET inhibitor adefovir is able to partially rescue chemotaxis.…”

Section: Immunological Effectsmentioning

confidence: 99%

“…This suggests that the delivery of spores to the lymph node is not sufficient for a disseminated infection in the subcutaneous route. Lastly, the production of LT in the ear of the mouse led to decreased neutrophil accumulation in the ear [184,193]. Given the conserved targets in immune cells, it is likely that macrophages are also less able to chemotax toward the infection to the ear when the bacteria are producing LT. As such, there would be fewer phagocytes to deliver the bacilli to the draining lymph node in a subcutaneous infection.…”

Section: The Effect Of the Portal Of Entry On B Anthracis Disseminationmentioning

confidence: 99%

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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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Anthrax Toxins

Moayeri

Leppla

2010

Bacillus Anthracis and Anthrax

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Anthrax toxins inhibit immune cell chemotaxis by perturbing chemokine receptor signalling

Cited by 69 publications

References 23 publications

Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

Analysis of Defined Combinations of Monoclonal Antibodies in Anthrax Toxin Neutralization Assays and Their Synergistic Action

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

Anthrax Toxins

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