Effect of Bacillus anthracis virulence factors on human dendritic cell activation

Hahn, Andrew C.; Lyons, C. Rick; Lipscomb, Mary F.

doi:10.1016/j.humimm.2008.06.012

Cited by 12 publications

(13 citation statements)

References 50 publications

(74 reference statements)

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“…This poorly immunogenic outermost layer may also shield more reactogenic bacterial factors on intact bacilli, such as PGN, from being sensed by pattern recognition receptors on host cells. In support of this hypothesis, it has been shown that human primary myeloid DCs and human monocyte-derived DCs release less IL-12p40, IL-6, and TNF-␣ when they are cocultured with an encapsulated strain of B. anthracis than when they are cocultured with an unencapsulated strain (47). Our results indicate that the capsule may not need to be bound to the bacilli in order to protect them from the immune system.…”

Section: Discussionsupporting

confidence: 76%

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

et al. 2014

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The antiphagocytic capsule of Bacillus anthracis is a major virulence factor. We hypothesized that it may also mediate virulence through inhibition of the host's immune responses. During an infection, the capsule exists attached to the bacterial surface but also free in the host tissues. We sought to examine the impact of free capsule by assessing its effects on human monocytes and immature dendritic cells (iDCs). Human monocytes were differentiated into iDCs by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) over 7 days in the presence of capsule derived from wild-type encapsulated B. anthracis Ames (WT) or a control preparation from an isogenic B. anthracis Ames strain that produces only 2% of the capsule of the WT (capA mutant). WT capsule consistently induced release of IL-8 and IL-6 while the capA mutant control preparation elicited either no response or only a minimal release of IL-8. iDCs that were differentiated in the presence of WT capsule had increased side scatter (SSC), a measure of cellular complexity, when assessed by flow cytometry. iDCs differentiated in the presence of WT capsule also matured less well in response to subsequent B. anthracis peptidoglycan (Ba PGN) exposure, with reduced upregulation of the chemokine receptor CCR7, reduced CCR7-dependent chemotaxis, and reduced release of certain cytokines. Exposure of naive differentiated control iDCs to WT capsule did not alter cell surface marker expression but did elicit IL-8. These results indicate that free capsule may contribute to the pathogenesis of anthrax by suppressing the responses of immune cells and interfering with the maturation of iDCs. Bacillus anthracis is the causative agent of anthrax and an important biothreat agent. The virulence of B. anthracis derives primarily from the products of two plasmids, pX01, which carries the genes for lethal toxin and edema toxin (1), and pX02, which carries the genes required for synthesizing capsule (2, 3). B. anthracis capsule covers the outer surface of the bacilli and protects them from phagocytosis by immune cells (4-6). While most bacterial capsules are polysaccharides, B. anthracis capsule is a homopolymer composed entirely of D-glutamic acid residues connected by ␥ linkages (7). These unusual attributes make B. anthracis capsule both relatively resistant to degradation by mammalian proteases and a poorly immunogenic thymus-independent type 2 antigen (8, 9).In in vitro broth culture and during infection, B. anthracis bacilli release capsule fragments. These free capsule fragments can accumulate to significant concentrations in the blood of moribund animals (7). Serum concentrations of B. anthracis capsule greater than 500 g/ml have been reported in mice (10), and concentrations greater than 1 mg/ml have been reported in rhesus macaques (11). Concentrations in local lesions could potentially be as high or even higher. Capsule free from the bacillus has been demonstrated to accumulate in animal tissues (12, 13). Early experiments with capsule recovered ...

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Section: Discussionsupporting

confidence: 76%

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

et al. 2014

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“…Two independent studies showed that, similar to the findings on mouse-derived DC, LT and ET impair cytokine secretion by human MoDCs or primary blood DCs (Brittingham et al, 2005;Hahn et al, 2008). ET also disrupts monocyte (Hoover et al, 1994) and DC Tournier et al, 2005) functions, alone or in cooperation with LT.…”

Section: At the Boundary Between Innate And Adaptive Immunity: Anthramentioning

confidence: 66%

Anthrax toxins: A weapon to systematically dismantle the host immune defenses

Tournier

Paccani

Quesnel‐Hellmann

et al. 2009

Molecular Aspects of Medicine

116

125

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“…However, because PA is required for both toxins to function, it is unclear whether the protective effect of anti-PA antibody is primarily due to the neutralization of LT and/or ET. Studies examining the effects of pure LT and/or ET directly on cells in vitro, or injection of pure toxin in animals have revealed several potential mechanisms by which LF and EF may exert their toxic effects, including immunomodulatory effects on cells of the immune system, induction of apoptosis, and direct tissue damage (11,14,18,23,31,47,53,54,59,62,71). Nevertheless, the pathophysiological roles and relative importance of the individual toxins produced during an infection with B. anthracis remains uncertain.…”

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confidence: 99%

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

et al. 2012

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ABSTRACTThe development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. The rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics againstBacillus anthracis. We investigated the roles ofB. anthraciscapsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the Ames strain versus isogenic mutants with deletions of the genes for the capsule operon (capBCADE), lethal factor (lef), edema factor (cya), or protective antigen (pagA). The absence of capsule or protective antigen (PA) resulted in complete avirulence, while the presence of either edema toxin or lethal toxin plus capsule resulted in lethality. The absence of toxin did not influence the ability ofB. anthracisto traffic to draining lymph nodes, but systemic dissemination required the presence of at least one of the toxins. Histopathology studies demonstrated minimal differences among lethal wild-type and single toxin mutant strains. When rabbits were coinfected with the Ames strain and the PA− mutant strain, the toxin produced by the Ames strain was not able to promote dissemination of the PA− mutant, suggesting that toxigenic action occurs in close proximity to secreting bacteria. Taken together, these findings suggest that a major role for toxins in the pathogenesis of anthrax is to enable the organism to overcome innate host effector mechanisms locally and that much of the damage during the later stages of infection is due to the interactions of the host with the massive bacterial burden.

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Effect of Bacillus anthracis virulence factors on human dendritic cell activation

Cited by 12 publications

References 50 publications

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

Exposure to Bacillus anthracis Capsule Results in Suppression of Human Monocyte-Derived Dendritic Cells

Anthrax toxins: A weapon to systematically dismantle the host immune defenses

Expression of either Lethal Toxin or Edema Toxin by Bacillus anthracis Is Sufficient for Virulence in a Rabbit Model of Inhalational Anthrax

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