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Infection and Immunity, January 2009, p. 162-169, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00788-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Sequential B-Cell Epitopes of Bacillus anthracis Lethal Factor Bind Lethal Toxin-Neutralizing Antibodies{triangledown}

Melissa L. Nguyen,1,2 Sherry R. Crowe,2 Sridevi Kurella,2 Simon Teryzan,3 Brian Cao,4 Jimmy D. Ballard,1 Judith A. James,2 and A. Darise Farris1,2*

Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104,1 Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104,2 Crystallography Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104,3 Laboratory of Antibody Technology, Van Andel Research Institute, Grand Rapids, Michigan 495034

Received 23 June 2008/ Returned for modification 18 July 2008/ Accepted 20 October 2008

The bipartite anthrax lethal toxin (LeTx) consisting of protective antigen (PA) and lethal factor (LF) is a major virulence factor contributing to death from systemic Bacillus anthracis infection. The current vaccine elicits antibodies directed primarily to PA; however, in experimental settings serologic responses to LF can neutralize LeTx and contribute to protection against infection. The goals of the present study were to identify sequential B-cell epitopes of LF and to determine the capacity of these determinants to bind neutralizing antibodies. Sera of recombinant LF-immunized A/J mice exhibited high titers of immunoglobulin G anti-LF reactivity that neutralized LeTx in vitro 78 days after the final booster immunization and protected the mice from in vivo challenge with 3 50% lethal doses of LeTx. These sera bound multiple discontinuous epitopes, and there were major clusters of reactivity on native LF. Strikingly, all three neutralizing, LF-specific monoclonal antibodies tested bound specific peptide sequences that coincided with sequential epitopes identified in polyclonal antisera from recombinant LF-immunized mice. This study confirms that LF induces high-titer protective antibodies in vitro and in vivo. Moreover, the binding of short LF peptides by LF-specific neutralizing monoclonal antibodies suggests that generation of protective antibodies by peptide vaccination may be feasible for this antigen. This study paves the way for a more effective anthrax vaccine by identifying discontinuous peptide epitopes of LF.

* Corresponding author. Mailing address: Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104. Phone: (405) 271-7389. Fax: (405) 271-4110. E-mail: darise-farris{at}omrf.org

{triangledown} Published ahead of print on 3 November 2008.

Editor: B. A. McCormick

Infection and Immunity, January 2009, p. 162-169, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00788-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kelly-Cirino, C. D., Mantis, N. J. (2009). Neutralizing Monoclonal Antibodies Directed against Defined Linear Epitopes on Domain 4 of Anthrax Protective Antigen. Infect. Immun. 77: 4859-4867 [Abstract] [Full Text]  
  • Nguyen, M. L., Terzyan, S., Ballard, J. D., James, J. A., Farris, A. D. (2009). The Major Neutralizing Antibody Responses to Recombinant Anthrax Lethal and Edema Factors Are Directed to Non-Cross-Reactive Epitopes. Infect. Immun. 77: 4714-4723 [Abstract] [Full Text]  


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