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Review
. 2012 Oct;4(10):878-99.
doi: 10.3390/toxins4100878. Epub 2012 Oct 19.

Anthrax lethal toxin and the induction of CD4 T cell immunity

Stephanie Ascough  1 , Rebecca J Ingram, Daniel M Altmann
Affiliations
Review

Anthrax lethal toxin and the induction of CD4 T cell immunity

Stephanie Ascough et al. Toxins (Basel). 2012 Oct.

Abstract

Bacillus anthracis secretes exotoxins which act through several mechanisms including those that can subvert adaptive immunity with respect both to antigen presenting cell and T cell function. The combination of Protective Antigen (PA) and Lethal Factor (LF) forming Lethal Toxin (LT), acts within host cells to down-regulate the mitogen activated protein kinase (MAPK) signaling cascade. Until recently the MAPK kinases were the only known substrate for LT; over the past few years it has become evident that LT also cleaves Nlrp1, leading to inflammasome activation and macrophage death. The predicted downstream consequences of subverting these important cellular pathways are impaired antigen presentation and adaptive immunity. In contrast to this, recent work has indicated that robust memory T cell responses to B. anthracis antigens can be identified following natural anthrax infection. We discuss how LT affects the adaptive immune response and specifically the identification of B. anthracis epitopes that are both immunogenic and protective with the potential for inclusion in protein sub-unit based vaccines.

Keywords: CD4 T cell; anthrax; epitope; lethal factor; protective antigen; vaccine.

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Figures

Figure 1
Figure 1
A schematic ribbon diagram depicting the Lethal Factor protein. Within the domain IV catalytic center we have identified a number of T cell epitopes, represented in white [49]. LF is capable of inactivating key cellular pathways, as the majority of these functions are related to the active center, epitopes within this region may prove crucial in the development of a vaccine capable of successfully inhibiting the toxin. This figure was generated using the Accelrys discovery studio client 2.5 program.
Figure 2
Figure 2
Model of cellular intoxication by LT. The 83 kDa PA protein secreted by B. anthracis binds to the host cell surface receptor (ANTXR1/TEM8, ANTXR2/CMG2 or the integrins α4β1 and α5β1), and is proteolytically cleaved by host furin, releasing a 20 kDa fragment from the N-terminal of the protein. The remaining 63 kDa PA fragment heptamerises and binds to LF to form LT. The toxins are then internalised in endosomal vesicles which are subsequently acidified, triggering the translocation of LT into the host cytosol. LT inactivates the MKKs, the central step in the MAPK signaling pathway, and induces the Nlrp1 activation of the inflammasome.
See this image and copyright information in PMC

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