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Infection and Immunity, January 2009, p. 274-285, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00515-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Four Superoxide Dismutases Contribute to Bacillus anthracis Virulence and Provide Spores with Redundant Protection from Oxidative Stress{triangledown} ,{dagger}

Robert J. Cybulski Jr.,1 Patrick Sanz,1 Farhang Alem,1 Scott Stibitz,2 Robert L. Bull,3,{ddagger} and Alison D. O'Brien1*

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799,1 FDA CBER, Division of Bacterial, Parasitic and Allergenic Products, NIH Campus Building 29, Room 201, HFM-440, Bethesda, Maryland 20892,2 Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, Maryland 209103

Received 25 April 2008/ Returned for modification 22 June 2008/ Accepted 16 October 2008

The Bacillus anthracis genome encodes four superoxide dismutases (SODs), enzymes capable of detoxifying oxygen radicals. That two of these SODs, SOD15 and SODA1, are present in the outermost layers of the B. anthracis spore is indicated by previous proteomic analyses of the exosporium. Given the requirement that spores must survive interactions with reactive oxygen species generated by cells such as macrophages during infection, we hypothesized that SOD15 and SODA1 protect the spore from oxidative stress and contribute to the pathogenicity of B. anthracis. To test these theories, we constructed a double-knockout ({Delta}sod15 {Delta}sodA1) mutant of B. anthracis Sterne strain 34F2 and assessed its lethality in an A/J mouse intranasal infection model. The 50% lethal dose of the {Delta}sod15 {Delta}sodA1 strain was similar to that of the wild type (34F2), but surprisingly, measurable whole-spore SOD activity was greater than that in 34F2. A quadruple-knockout strain ({Delta}sod15 {Delta}sodA1 {Delta}sodC {Delta}sodA2) was then generated, and as anticipated, spore-associated SOD activity was diminished. Moreover, the quadruple-knockout strain, compared to the wild type, was attenuated more than 40-fold upon intranasal challenge of mice. Spore resistance to exogenously generated oxidative stress and to macrophage-mediated killing correlated with virulence in A/J mice. Allelic exchange that restored sod15 and sodA1 to their wild-type state restored wild-type characteristics. We conclude that SOD molecules within the spore afford B. anthracis protection against oxidative stress and enhance the pathogenicity of B. anthracis in the lung. We also surmise that the presence of four SOD alleles within the genome provides functional redundancy for this key enzyme.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799. Phone: (301) 295-3400. Fax: (301) 295-3773. E-mail: aobrien{at}usuhs.mil

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

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

Editor: F. C. Fang

{ddagger} Present address: FBI Laboratory, 2501 Investigation Parkway, Quantico, VA 22135.

Infection and Immunity, January 2009, p. 274-285, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00515-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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