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Infection and Immunity, December 2007, p. 5726-5734, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00727-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effects of Endogenous D-Alanine Synthesis and Autoinhibition of Bacillus anthracis Germination on In Vitro and In Vivo Infections{triangledown}

Matthew T. McKevitt,1,{dagger} Katie M. Bryant,1 Salika M. Shakir,1 Jason L. Larabee,1 Steven R. Blanke,2 Julie Lovchik,3 C. Rick Lyons,3 and Jimmy D. Ballard1*

Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104,1 Department of Microbiology and the Institute for Genomic Biology, University of Illinois, Urbana, Illinois 68101,2 Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 871313

Received 29 May 2007/ Returned for modification 8 July 2007/ Accepted 10 September 2007

Bacillus anthracis transitions from a dormant spore to a vegetative bacillus through a series of structural and biochemical changes collectively referred to as germination. The timing of germination is important during early steps in infection and may determine if B. anthracis survives or succumbs to responsive macrophages. In the current study experiments determined the contribution of endogenous D-alanine production to the efficiency and timing of B. anthracis spore germination under in vitro and in vivo conditions. Racemase-mediated production of endogenous D-alanine by B. anthracis altered the kinetics for initiation of germination over a range of spore densities and exhibited a threshold effect wherein small changes in spore number resulted in major changes in germination efficiency. This threshold effect correlated with D-alanine production, was prevented by an alanine racemase inhibitor, and required L-alanine. Interestingly, endogenous production of inhibitory levels of D-alanine was detected under experimental conditions that did not support germination and in a germination-deficient mutant of B. anthracis. Racemase-dependent production of D-alanine enhanced survival of B. anthracis during interaction with murine macrophages, suggesting a role for inhibition of germination during interaction with these cells. Finally, in vivo experiments revealed an approximately twofold decrease in the 50% lethal dose of B. anthracis spores administered in the presence of D-alanine, indicating that rates of germination may be directly influenced by the levels of this amino acid during early stages of disease.

* Corresponding author. Mailing address: University of Oklahoma Health Sciences Center, BRC-362A, 975 NE 10th Street, Oklahoma City, OK 73104. Phone: (405) 271-3855. Fax: (405) 271-3874. E-mail: jimmy-ballard{at}ouhsc.edu

{triangledown} Published ahead of print on 8 October 2007.

Editor: A. Camilli

{dagger} Present address: Department of Genome Sciences, University of Washington, Seattle, WA 98195.

Infection and Immunity, December 2007, p. 5726-5734, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00727-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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