Anthrax prophylaxis: recent advances and future directions

Abstract

Anthrax is a serious, potentially fatal disease that can present in four distinct clinical patterns depending on the route of infection (cutaneous, gastrointestinal, pneumonic, or injectional); effective strategies for prophylaxis and therapy are therefore required. This review addresses the complex mechanisms of pathogenesis employed by the bacterium and describes how, as understanding of these has developed over many years, so too have current strategies for vaccination and therapy. It covers the clinical and veterinary use of live attenuated strains of anthrax and the subsequent identification of protein sub-units for incorporation into vaccines, as well as combinations of protein sub-units with spore or other components. It also addresses the application of these vaccines for conventional prophylactic use, as well as post-exposure use in conjunction with antibiotics. It describes the licensed acellular vaccines AVA and AVP and discusses the prospects for a next generation of recombinant sub-unit vaccines for anthrax, balancing the regulatory requirement and current drive for highly defined vaccines, against the risk of losing the "danger" signals required to induce protective immunity in the vaccinee. It considers novel approaches to reduce time to immunity by means of combining, for example, dendritic cell vaccination with conventional approaches and considers current opportunities for the immunotherapy of anthrax.

Keywords: MAP kinase; adenylate cyclase; anthrax; pathogenesis; prophylaxis; therapy; toxemia.

Figure 1

Delivery of LF and EF into the host cell. PA 83 binds to cell surface receptors and is subsequently cleaved and oligomerises to form a heptamer (PA^7mer). LF and EF can bind to the PA^7mer to form lethal toxin (LT) or edema toxin (ET) which associate with lipid rafts. These complexes are endocytosed (in clathrin-coated pits, facilitated by LRP6) and enter early endosomes. Subsequently, LT/ET are conveyed in vesicles to late perinuclear endosomes. The PA^7mer forms a pore in the vesicle luminal wall, releasing EF to the membrane and LF to the cytosol. EF creates a gradient of cAMP emanating from the nucleus to the cell wall, whilst LF cleaves the MAP/ERK kinase (MEK) substrate to inhibit nuclear protein synthesis. Glossary: MAPKKs, mitogen-activated protein kinase kinases; ERKK, extracellular-signal-regulated kinases; MEK, MAP/ERK kinases.

Figure 2

Opposing effects of anthrolysin, LF and EF on host cell apoptosis. Anthrolysin secreted by B. anthracis binds surface TLR4 receptors with downstream signaling through either TRIF and PKR to promote apoptosis, or through MEK to inhibit apoptosis; the latter inhibitory effect is opposed by LF cleaving MEK, thus promoting apoptosis. EF signals through the PKA and CREB pathway which has benefit in delaying apoptosis until the phagocytic host cell reaches the lymph node, an optimal niche for germination with further toxin release. Glossary: PKR, protein kinase regulated by RNA; PKA protein kinase A; CREB, cAMP response-element-binding protein; TRIF, TIR-domain-containing adapter-inducing interferon-β.