Abstract
Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.
Highlights
Bacillus anthracis secretes an 83 kDa protein, known as protective Ag (PA), that forms heptameric pores on the surface of target cells expressing anthrax toxin receptors [1,2]
PA heptamers interact with lethal factor (LF) and edema factor (EF) to form lethal toxin (LT) and edema toxin (ET), respectively, which together are known as anthrax toxin [2]
It was reported that LF and EF result in lethality in mice via the cardiac and hepatic systems respectively [10]
Summary
Bacillus anthracis secretes an 83 kDa protein, known as protective Ag (PA), that forms heptameric pores on the surface of target cells expressing anthrax toxin receptors (capillary morphogenesis protein-2, CMG-2 and tumor endothelial marker-8,TEM-8) [1,2]. PA heptamers interact with lethal factor (LF) and edema factor (EF) to form lethal toxin (LT) and edema toxin (ET), respectively, which together are known as anthrax toxin [2]. The PA heptamer facilitates entry of EF and LF into the target cell. Within the target cell LF functions as a zinc-dependent metalloprotease and cleaves mitogen activated protein kinase kinases [3]. EF, which has calmodulin-dependent adenylate cyclase activity, generates high concentrations of cAMP [4]. LT and ET have potent immune-subversive effects during the early stages of infection, inhibiting the functions of dendritic cells,
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.