Abstract
Soluble receptor decoy inhibitors, including receptor-immunogloubulin (Ig) fusion proteins, have shown promise as candidate anthrax toxin therapeutics. These agents act by binding to the receptor-interaction site on the protective antigen (PA) toxin subunit, thereby blocking toxin binding to cell surface receptors. Here we have made the surprising observation that co-administration of receptor decoy-Ig fusion proteins significantly delayed, but did not protect, rats challenged with anthrax lethal toxin. The delayed toxicity was associated with the in vivo assembly of a long-lived complex comprised of anthrax lethal toxin and the receptor decoy-Ig inhibitor. Intoxication in this system presumably results from the slow dissociation of the toxin complex from the inhibitor following their prolonged circulation. We conclude that while receptor decoy-Ig proteins represent promising candidates for the early treatment of B. anthracis infection, they may not be suitable for therapeutic use at later stages when fatal levels of toxin have already accumulated in the bloodstream.
Highlights
Anthrax toxin is the major virulence factor of B. anthracis, the causative agent of anthrax
In an effort to improve the potency of the receptor decoy we set out to generate a long-lived fusion protein comprised of the ANTXR2 von Willebrand Factor type A (VWA) domain fused to the Fc portion of an IgG1 antibody, since that is a commonly used strategy to increase serum half-life of proteins
Delayed toxicity was completely dependent upon the addition of lethal factor (LF) since no toxicity was observed with the receptor decoy-Ig protein and protective antigen (PA) alone
Summary
Anthrax toxin is the major virulence factor of B. anthracis, the causative agent of anthrax. The first step of intoxication involves binding of an 83 kD form of PA (PA83) to cell surface receptors. Following receptor-binding, PA83 is cleaved to a 63 kD form by a cell surface furin-like protease, and the resultant PA63 fragment spontaneously assembles into either heptameric or octameric prepore complexes [6,7,8,9]. These oligomeric PA complexes may assemble prior to receptor binding following PA83 to PA63 cleavage by a serum protease within the bloodstream of infected animals [10,11]. Entry into an acidic endosomal compartment stimulates PA63 prepore-topore conversion and LF and EF translocation into the cytosol leading to toxicity [16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: 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.
