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Infection and Immunity, January 2009, p. 255-265, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00633-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Anthrax Toxins in Dissemination, Disease Progression, and Induction of Protective Adaptive Immunity in the Mouse Aerosol Challenge Model{triangledown} ,{dagger}

Crystal L. Loving,1,{ddagger} Taruna Khurana,1 Manuel Osorio,2 Gloria M. Lee,1 Vanessa K. Kelly,1 Scott Stibitz,2 and Tod J. Merkel1*

Laboratory of Respiratory and Special Pathogens,1 Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, Maryland 208922

Received 22 May 2008/ Returned for modification 30 July 2008/ Accepted 16 October 2008

Anthrax toxins significantly contribute to anthrax disease pathogenesis, and mechanisms by which the toxins affect host cellular responses have been identified with purified toxins. However, the contribution of anthrax toxin proteins to dissemination, disease progression, and subsequent immunity after aerosol infection with spores has not been clearly elucidated. To better understand the role of anthrax toxins in pathogenesis in vivo and to investigate the contribution of antibody to toxin proteins in protection, we completed a series of in vivo experiments using a murine aerosol challenge model and a collection of in-frame deletion mutants lacking toxin components. Our data show that after aerosol exposure to Bacillus anthracis spores, anthrax lethal toxin was required for outgrowth of bacilli in the draining lymph nodes and subsequent progression of infection beyond the lymph nodes to establish disseminated disease. After pulmonary exposure to anthrax spores, toxin expression was required for the development of protective immunity to a subsequent lethal challenge. However, immunoglobulin (immunoglobulin G) titers to toxin proteins, prior to secondary challenge, did not correlate with the protection observed upon secondary challenge with wild-type spores. A correlation was observed between survival after secondary challenge and rapid anamnestic responses directed against toxin proteins. Taken together, these studies indicate that anthrax toxins are required for dissemination of bacteria beyond the draining lymphoid tissue, leading to full virulence in the mouse aerosol challenge model, and that primary and anamnestic immune responses to toxin proteins provide protection against subsequent lethal challenge. These results provide support for the utility of the mouse aerosol challenge model for the study of inhalational anthrax.

* Corresponding author. Mailing address: Laboratory of Respiratory and Special Pathogens, DBPAP/CBER/FDA, Bldg. 29, Rm. 418, 29 Lincoln Dr., Bethesda, MD 20892. Phone: (301) 496-5564. Fax: (301) 402-2776. E-mail: merkel{at}cber.fda.gov

{triangledown} Published ahead of print on 27 October 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: V. J. DiRita

{ddagger} Present address: Respiratory Diseases of Livestock Research Unit, USDA/ARS/NADC, 2300 Dayton Avenue B13, Ames, IA 50010.

Infection and Immunity, January 2009, p. 255-265, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00633-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Loving, C. L., Osorio, M., Kim, Y.-G., Nunez, G., Hughes, M. A., Merkel, T. J. (2009). Nod1/Nod2-Mediated Recognition Plays a Critical Role in Induction of Adaptive Immunity to Anthrax after Aerosol Exposure. Infect. Immun. 77: 4529-4537 [Abstract] [Full Text]  


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