Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin

Abstract

Anthrax poses a clear and present danger as an agent of biological terrorism. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells--which are pivotal to the establishment of immunity against pathogens--and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response.

Anthrax Lethal Toxin Blocks MAPK Kinase-Dependent IL-2 Production in CD4+ T Cells

“…Recent studies have shown deleterious effects of the toxin not only on other types of APCs (e.g., dendritic cells) (25), but also on non-leukocytes such as human endothelial cells (26). Pro-apoptotic effects of anthrax LT treatment on unpurified human PBMC have been reported (14), but direct effects on purified T cells have not been previously demonstrated.…”

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

“…Several recent reports also suggest that the activation states of DC can be manipulated by pathogens, with significant implications for T cell priming. For instance, bacterial virulence factors from Bacillus anthracis impair in vivo DC function by disrupting intracellular signaling networks, thereby disarming adaptive immune responses [24]. On another level, TLR triggering on DC can block the suppressive effects of regulatory T cells by releasing specific cytokines [25].…”

Anthrax Lethal Toxin Kills Macrophages in a Strain-Specific Manner by Apoptosis or Caspase-1-Mediated Necrosis

“…It has been reported that LT treatment renders murine dendritic cells nonresponsive to LPS by inactivating MAPK signaling pathways. 11,25,26 Additionally, BALB/c-derived transformed macrophage lines are similarly nonresponsive to LPS stimulation following LT treatment. 51 We predicted that LT exposure has the same effect on slowly killed murine macrophages, and impairs the LPS response prior to the onset of cytopathic effects.…”

“…LT-mediated MAPKK cleavage, which renders specific cells nonresponsive to stimulation by mitogens, might further diminish the immune response. 11,[25][26][27] Immune impairment likely promotes bacterial proliferation in hosts infected with B. anthracis. [28][29][30][31] The susceptibility of murine macrophages to LT-mediated killing is strain-dependent.…”