Dendritic Cells Endocytose <i>Bacillus anthracis</i> Spores: Implications for Anthrax Pathogenesis

Brittingham, Katherine C.; Ruthel, Gordon; Panchal, Rekha G.; Fuller, Claudette L.; Ribot, Wilson J.; Hoover, Timothy A.; Young, Howard A.; Bavari, Sina

doi:10.4049/jimmunol.174.9.5545

Cited by 116 publications

(114 citation statements)

References 36 publications

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“…Previous investigators have added germination-proficient BA spores to macrophage and dendritic cell cultures under conditions that favored germination to bacillary forms and the expression of both LT and anthrolysin O, both of which have been associated with cell death [33][34][35]. This has made it difficult to differentiate between the effects of BA spores and vegetative bacilli on macrophage cytokine responses.…”

Section: Discussionmentioning

confidence: 99%

Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

et al. 2008

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Previous reports suggested that lethal toxin (LT)-induced caspase-1 activity and/or IL-1b accounted for Bacillus anthracis (BA) infection lethality. In contrast, we now report that caspase-1-mediated IL-1b expression in response to BA spores is required for anti-BA host defenses. Caspase-1 -/-and IL-1b -/-mice are more susceptible than wild-type (WT) mice to lethal BA infection, are less able to kill BA both in vivo and in vitro, and addition of rIL-1b to macrophages from these mice restored killing in vitro. Non-germinating BA spores induced caspase-1 activity, IL-1b and nitric oxide, by which BA are killed in WT but not in caspase-1 -/-mice, suggesting that the spore itself stimulated inflammatory responses.While spores induced IL-1b in LT-susceptible and -resistant macrophages, LT induced IL-1b only in LT-susceptible macrophages. Cooperation between MyD88-dependent and -independent signaling pathways was required for spore-induced, but not LT-induced, IL-1b. While both spores and LT induced caspase-1 activity and IL-1b, LT did not induce IL-1b mRNA, and spores did not induce cell death. Thus different components of the same bacterium each induce IL-1b by distinct signaling pathways. Whereas the spore-induced IL-1b limits BA infection, LT-induced IL-1b enables BA to escape host defenses.

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Section: Discussionmentioning

confidence: 99%

Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

et al. 2008

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“…The mechanisms involved in LDC migration to TLNs are not yet determined. Spores have been shown to trigger the reprogramming of chemokine expression by human DCs due to a loss of transcription in tissues retaining chemokine receptors (CCR2, CCR5) and due to the induction of lymph node homing receptor CCR7 gene transcription (42). It is likely that the recognition of sporal pathogen-associated molecular pattern by a MyD88-dependent mechanism (39) may also facilitate the reprogramming of chemokine receptors and increase the physiological migration of LDCs toward the draining TLNs.…”

Section: Discussionmentioning

confidence: 99%

Lung Dendritic Cells Rapidly Mediate Anthrax Spore Entry through the Pulmonary Route

Cleret

Quesnel‐Hellmann

Vallon-Eberhard

et al. 2007

The Journal of Immunology

138

121

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Inhalational anthrax is a life-threatening infectious disease of considerable concern, especially because anthrax is an emerging bioterrorism agent. The exact mechanisms leading to a severe clinical form through the inhalational route are still unclear, particularly how immobile spores are captured in the alveoli and transported to the lymph nodes in the early steps of infection. We investigated the roles of alveolar macrophages and lung dendritic cells (LDC) in spore migration. We demonstrate that alveolar macrophages are the first cells to phagocytose alveolar spores, and do so within 10 min. However, interstitial LDCs capture spores present in the alveoli within 30 min without crossing the epithelial barrier suggesting a specific mechanism for rapid alveolus sampling by transepithelial extension. We show that interstitial LDCs constitute the cell population that transports spores into the thoracic lymph nodes from within 30 min to 72 h after intranasal infection. Our results demonstrate that LDCs are central to spore transport immediately after infection. The rapid kinetics of pathogen transport may contribute to the clinical features of inhalational anthrax.

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“…In the initial stages of anthrax infection, toxin plays a role in facilitating spore germination (36)(37)(38). Once the vegetative infection is established, many cells are exposed to the toxin.…”

Section: Discussionmentioning

confidence: 99%

Receptor-specific requirements for anthrax toxin delivery into cells

Rainey

Wigelsworth

Ryan

et al. 2005

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

119

157

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The three proteins that constitute anthrax toxin self-assemble into toxic complexes after one of these proteins, protective antigen (PA), binds to tumor endothelial marker 8 (TEM8) or capillary morphogenesis protein 2 (CMG2) cellular receptors. The toxin receptor complexes are internalized, and acidic endosomal pH triggers pore formation by PA and translocation of the catalytic subunits into the cytosol. In this study we show that the pH threshold for conversion of the PA prepore to the pore and for translocation differs by approximately a pH unit, depending on whether the TEM8 or CMG2 receptor is used. For TEM8-associated toxin, these events can occur at close to neutral pH values, and they show relatively low sensitivity to ammonium chloride treatment in cells. In contrast, with CMG2-associated toxin, these events require more acidic conditions and are highly sensitive to ammonium chloride. We show, furthermore, that PA dissociates from TEM8 and CMG2 upon pore formation. Our results are consistent with a model in which translocation depends on pore formation and pore formation, in turn, depends on release of PA from its receptor. We propose that because PA binds to CMG2 with much higher affinity than it does to TEM8, a lower pH is needed to attenuate CMG2 binding to allow pore formation. Our results suggest that toxin can form pores at different points in the endocytic pathway, depending on which receptor is used for entry.capillary morphogenesis protein 2 ͉ tumor endothelial marker 8 ͉ toxin entry B acillus anthracis, the causative agent of anthrax, secretes a toxin that is believed to be instrumental in causing anthrax disease symptoms leading to death. Anthrax toxin consists of three proteins, protective antigen (PA), which is a receptorbinding and pore-forming subunit; lethal factor (LF), which is a protease that cleaves mitogen-activated protein kinase kinase family members; and edema factor (EF), which is an adenylate cyclase that raises cAMP levels in cells (1). PA is synthesized as an 83-kDa protein (PA 83 ) for which two cell surface receptors have been identified: tumor endothelial marker 8 (TEM8) (2, 3) and capillary morphogenesis protein 2 (CMG2) (4). Two splice variant mRNAs derived from the TEM8 gene (sv1 and sv2) encode functional anthrax toxin receptors (2, 5). TEM8 expression has been documented in epithelium of the lung, intestine, and skin, the three routes of entry in anthrax infection (6). The CMG2 gene, which has been shown to be broadly expressed in different tissues (4), encodes three protein isoforms, two of which, CMG2 488 and CMG2 489 , are anthrax toxin receptors (4) (H.M.S., unpublished data).Receptor-bound PA 83 is cleaved by a cellular protease to generate a 20-kDa PA 20 subunit and a 63-kDa subunit (PA 63 ). The larger subunit assembles into the heptameric (PA 63 ) 7 prepore in lipid rafts (7-9). EF and LF bind to the prepore, and the toxin-receptor complexes are internalized by clathrindependent endocytosis and by other endocytic mechanisms (9, 10). These complexes are then exp...

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Dendritic Cells Endocytose Bacillus anthracis Spores: Implications for Anthrax Pathogenesis

Cited by 116 publications

References 36 publications

Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

Bacillus anthracis spores and lethal toxin induce IL‐1β via functionally distinct signaling pathways

Lung Dendritic Cells Rapidly Mediate Anthrax Spore Entry through the Pulmonary Route

Receptor-specific requirements for anthrax toxin delivery into cells

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