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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

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.
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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.

Mentions: ET appears to have co-opted a host signaling pathway to facilitate the transport of bacteria from the lung to LNs. It is hypothesized that ET mimics the anti-inflammatory action of G-protein coupled receptors (GPCRs) to induce macrophage migration, ultimately delaying apoptosis and increasing the delivery of bacteria by macrophages to the LNs (Abrami et al., 2005, 2006; Tang and Guo, 2009; Guichard et al., 2011). Intracellularly, EF and LF appear to act synergistically to delay apoptosis. The pore-forming toxin anthrolysin binds TLR4 receptors, providing conflicting signals to induce apoptosis (via PKR) or to inhibit via MEK. However, by cleaving MEK's, LF blocks this inhibitory and protective signal, shifting the balance of TLR4 signaling toward apoptosis. EF counters this effect by signaling through the PKA and CREB pathways, protecting the macrophage during its migration to the LN where apoptosis occurs to release bacteria and spores (Figure 2), although this effect is not definitive and in some models ET has been proposed to inhibit macrophage migration (Guichard et al., 2011).


Anthrax prophylaxis: recent advances and future directions.

Williamson ED, Dyson EH - Front Microbiol (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

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

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.
Mentions: ET appears to have co-opted a host signaling pathway to facilitate the transport of bacteria from the lung to LNs. It is hypothesized that ET mimics the anti-inflammatory action of G-protein coupled receptors (GPCRs) to induce macrophage migration, ultimately delaying apoptosis and increasing the delivery of bacteria by macrophages to the LNs (Abrami et al., 2005, 2006; Tang and Guo, 2009; Guichard et al., 2011). Intracellularly, EF and LF appear to act synergistically to delay apoptosis. The pore-forming toxin anthrolysin binds TLR4 receptors, providing conflicting signals to induce apoptosis (via PKR) or to inhibit via MEK. However, by cleaving MEK's, LF blocks this inhibitory and protective signal, shifting the balance of TLR4 signaling toward apoptosis. EF counters this effect by signaling through the PKA and CREB pathways, protecting the macrophage during its migration to the LN where apoptosis occurs to release bacteria and spores (Figure 2), although this effect is not definitive and in some models ET has been proposed to inhibit macrophage migration (Guichard et al., 2011).

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