Bacillus anthracis vs. Dendritic Cells

Bacillus anthracis has been known as the causative agent of Anthrax since the late 19th century.1 While it is generally thought to be a bovine disease, Anthrax can strike all mammals including humans. B. anthracis is a gram-positive, spore-forming bacterium that secretes Anthrax toxin in the form of three proteins: Protective Antigen (PA83), named for its use as the Anthrax vaccine immunogen, Edema Factor (EF), and Lethal Factor (LF). The three proteins work in binary combinations called Edema Toxin (ET; PA and EF together) and Lethal Toxin (LT; PA and LF together).1 PA83 binds the cell surface Anthrax Toxin Receptor (ATR) expressed on a wide variety of mammalian cells2 and is subsequently cleaved at a basic residue stretch by the Ca2+-dependent serine protease, Furin, to yield the 63 kDa isoform (PA63).3 PA63 aggregates into a heptameric structure in plasma membrane lipid rafts, facilitating EF and LF internalization through a clathrin-dependent pathway.4 EF is a Ca2+/calmodulin-dependent adenylate cyclase, which has been shown to increase cAMP levels in macrophages, neutrophils, and lymphocytes,5 and LF is a zinc metalloprotease, which cleaves the N-termini of MAPK kinase (MEK) family members thereby reducing both their substrate affinities and kinase activities (Figure 1).6

Figure 1: B. anthracis secretes Anthrax toxin in the form of three proteins: Protective Antigen (PA83), Edema Factor (EF), and Lethal Factor (LF). PA83 binds the cell surface Anthrax Toxin Receptor (ATR) and is cleaved by Furin to yield PA63. PA63 forms a heptameric structure in the plasma membrane facilitating EF and LF internalization. EF is an adenylate cyclase, which increases intracellular cAMP, and LF is a metalloprotease, which cleaves MEK family members.

While our understanding of the nature of the Anthrax toxin itself has improved over recent years, many questions regarding the mechanisms of Anthrax pathogenicity remain unanswered.1,7,8 Most of the work on Anthrax has been performed on macrophages, since they are dramatically affected by Antrax infection. In vitro, LT enters primary mouse macrophages and various mouse macrophage cell lines and elicits cytolysis within hours. Although LT is known to enter many other cell types, none of them appear to be affected.7 Recent events have increased concern about the use of Anthrax as a biological weapon. As a result, Anthrax research has accelerated, contributing significantly to our understanding of Anthrax pathogenicity. A new report by Agrawal et al. offers the first evidence that dendritic cells (DCs) are also a major target of B. anthracis.9 Unlike macrophages, DCs survive LT exposure, although they are functionally impaired. At the cellular level, LT treatment significantly reduces LPS-induced B7-1, B7-2, and CD40 costimulatory molecule upregulation and IL-1 alpha, IL-6, IL-12, and TNF-alpha cytokine secretion in vitro. Further, LT-treated DCs were incapable of priming naive CD4+ T cells in vitro and in vivo, and this impaired T cell activation resulted in depressed B cell responses in vivo.9 At the molecular level, LF treatment inhibits p38 and ERK phosphorylation in DCs, and synthetic MAP kinase inhibitors can mimic these effects. Further, a mutant form of LF that is incapable of cleaving MEK fails to affect DC function.9 Collectively these data suggest that Anthrax LT is capable of severely depressing T and B cell responses by impairing the function of a major antigen presenting cell type. Not only does this imply that bacterial infection containment is compromised but also that survivors of Anthrax infection would be more susceptible to subsequent unrelated infections.9 Until recently, the inhalation form of Anthrax was almost uniformly fatal. However, several people that contracted inhalation Anthrax during the 2001 U.S. mail attacks have survived. It will be of interest to examine the long term effects of Anthrax exposure on overall health.8


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  2. Bradley, K.A. et al. (2001) Nature 414:225.
  3. Henrich, S. et al. (2003) Nat. Struct. Biol. 10:520.
  4. Abrami, L. et al. (2003) J. Cell Biol. 160:321.
  5. Kumar, P. et al. (2002) Infect. Immun. 70:4997.
  6. Chopra, A.P. et al. (2003) J. Biol. Chem. 278:9402.
  7. Guidi-Rontani, C. & M. Mock (2002) Curr. Top. Microbiol. Immunol. 271:115.
  8. Starnbach, M.N. & R.J. Collier (2003) Nat. Med. 9:996.
  9. Agrawal, A. et al. (2003) Nature 424:329.