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Anthrax prophylaxis: recent advances and future directions.

Williamson ED, Dyson EH - Front Microbiol (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Defence Science and Technology Laboratory Porton Down, Salisbury, UK.

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.

No MeSH data available.


Related in: MedlinePlus

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 (PA7mer). LF and EF can bind to the PA7mer 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 PA7mer 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.
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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 (PA7mer). LF and EF can bind to the PA7mer 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 PA7mer 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.

Mentions: Much is now known about the process of host cell-binding by PA prior to endocytosis of either of these toxic complexes (Abrami et al., 2005). The full-length (83 kDa) PA binds to one or more host cell receptors: Capillary Morphogenesis factor 2 (CMG2), Trans-endothelial membrane receptor 8 (TEM8), or β1-integrin (Martchenko et al., 2010). It then undergoes furin cleavage to release a 20 kDa N-terminal fragment, leaving a 63 kDa truncated protein (PA63) which is subject to a structural rearrangement with heptamerisation, so that domain 4 is in contact with the host cell receptor. In the process, binding sites for either three molecules of LF or EF are exposed on units of the PA heptamer (a maximum of nine toxic complexes are generated per PA 7mer) and the latter associates with lipid rafts, mediated by the lipoprotein-receptor-related protein 6 (LRP6; Wei et al., 2006). Subsequently, the toxic complex undergoes clathrin-mediated endocytosis (Abrami et al., 2010) and enters early endosomes where it is incorporated into intraluminal vesicles (Figure 1). Acidification of the endosome allows insertion of the PA7mer into the membrane of the intraluminal vesicles as well as the unfolding and release of LF and EF through the channel of the PA7mer, into the lumen of the vesicle. Subsequently, both LF and EF undergo microtubular transport through the lumen of the vesicles to late perinuclear endosomes. Here, the vesicles can undergo back fusion with the limiting membrane so that LF is released into the perinuclear cytoplasm (Liu et al., 2003; Abrami et al., 2006; van der Goot and Young, 2009) where it cleaves MAPKKs to disrupt phosphorylation and transcription in the nucleus, ultimately preventing protein synthesis and causing cell death. EF, a calcium and calmodulin-dependent adenylate cyclase, remains bound to late perinuclear endosomes, where it causes a rapid increase in perinuclear cAMP resulting in cellular, tissue and ultimately organ oedema (Tang and Guo, 2009).


Anthrax prophylaxis: recent advances and future directions.

Williamson ED, Dyson EH - Front Microbiol (2015)

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 (PA7mer). LF and EF can bind to the PA7mer 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 PA7mer 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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585224&req=5

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 (PA7mer). LF and EF can bind to the PA7mer 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 PA7mer 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.
Mentions: Much is now known about the process of host cell-binding by PA prior to endocytosis of either of these toxic complexes (Abrami et al., 2005). The full-length (83 kDa) PA binds to one or more host cell receptors: Capillary Morphogenesis factor 2 (CMG2), Trans-endothelial membrane receptor 8 (TEM8), or β1-integrin (Martchenko et al., 2010). It then undergoes furin cleavage to release a 20 kDa N-terminal fragment, leaving a 63 kDa truncated protein (PA63) which is subject to a structural rearrangement with heptamerisation, so that domain 4 is in contact with the host cell receptor. In the process, binding sites for either three molecules of LF or EF are exposed on units of the PA heptamer (a maximum of nine toxic complexes are generated per PA 7mer) and the latter associates with lipid rafts, mediated by the lipoprotein-receptor-related protein 6 (LRP6; Wei et al., 2006). Subsequently, the toxic complex undergoes clathrin-mediated endocytosis (Abrami et al., 2010) and enters early endosomes where it is incorporated into intraluminal vesicles (Figure 1). Acidification of the endosome allows insertion of the PA7mer into the membrane of the intraluminal vesicles as well as the unfolding and release of LF and EF through the channel of the PA7mer, into the lumen of the vesicle. Subsequently, both LF and EF undergo microtubular transport through the lumen of the vesicles to late perinuclear endosomes. Here, the vesicles can undergo back fusion with the limiting membrane so that LF is released into the perinuclear cytoplasm (Liu et al., 2003; Abrami et al., 2006; van der Goot and Young, 2009) where it cleaves MAPKKs to disrupt phosphorylation and transcription in the nucleus, ultimately preventing protein synthesis and causing cell death. EF, a calcium and calmodulin-dependent adenylate cyclase, remains bound to late perinuclear endosomes, where it causes a rapid increase in perinuclear cAMP resulting in cellular, tissue and ultimately organ oedema (Tang and Guo, 2009).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Defence Science and Technology Laboratory Porton Down, Salisbury, UK.

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.

No MeSH data available.


Related in: MedlinePlus