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Infection and Immunity, November 2009, p. 5181-5189, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00231-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Nondividing but Metabolically Active Gamma-Irradiated Brucella melitensis Is Protective against Virulent B. melitensis Challenge in Mice{triangledown}

D. M. Magnani, J. S. Harms, M. A. Durward, and G. A. Splitter*

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706

Received 26 February 2009/ Returned for modification 2 April 2009/ Accepted 17 August 2009

Brucella spp. are gram-negative bacteria that cause the most frequent zoonotic disease worldwide, with more than 500,000 human infections yearly; however, no human vaccine is currently available. As with other intracellular organisms, cytotoxic mechanisms against infected cells are thought to have an important role in controlling infection and mediating long-term immunity. Live attenuated strains developed for use in animals elicit protection but retain unacceptable levels of virulence. Thus, the optimal design for a brucellosis vaccine requires a nonliving vaccine that confers effective immunity. Historically, inactivation methods such as chemical or heat treatment successfully impair Brucella reproductive capacity; nevertheless, metabolically inactive vaccines (subunit or killed) present very limited efficacy. Hence, we hypothesized that bacterial metabolism plays a major role in creating the proper antigenic and adjuvant properties required for efficient triggering of protective responses. Here, we demonstrate that inactivation of Brucella melitensis by gamma-irradiation inhibited its replication capability and yet retained live-Brucella protective features. Irradiated Brucella possessed metabolic and transcriptional activity, persisted in macrophages, generated antigen-specific cytotoxic T cells, and protected mice against virulent bacterial challenge, without signs of residual virulence. In conclusion, pathogen metabolic activity has a positive role in shaping protective responses, and the generation of inactivated and yet metabolically active microbes is a promising strategy for safely vaccinating against intracellular organisms such as B. melitensis.

* Corresponding author. Mailing address: University of Wisconsin-Madison, AHABS, 1656 Linden Drive, Madison, WI 53706. Phone: (608) 262-1837. Fax: (608) 262-7420. E-mail: splitter{at}svm.vetmed.wisc.edu

{triangledown} Published ahead of print on 24 August 2009.

Editor: R. P. Morrison

Infection and Immunity, November 2009, p. 5181-5189, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00231-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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