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That two of these SODs, SOD15 and SODA1, are present in the outermost layers of the\n            <jats:italic>B. anthracis<\/jats:italic>\n            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\n            <jats:italic>B. anthracis<\/jats:italic>\n            . To test these theories, we constructed a double-knockout (\u0394\n            <jats:italic>sod15<\/jats:italic>\n            \u0394\n            <jats:italic>sodA1<\/jats:italic>\n            ) mutant of\n            <jats:italic>B. anthracis<\/jats:italic>\n            Sterne strain 34F2 and assessed its lethality in an A\/J mouse intranasal infection model. The 50% lethal dose of the \u0394\n            <jats:italic>sod15<\/jats:italic>\n            \u0394\n            <jats:italic>sodA1<\/jats:italic>\n            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 (\u0394\n            <jats:italic>sod15<\/jats:italic>\n            \u0394\n            <jats:italic>sodA1<\/jats:italic>\n            \u0394\n            <jats:italic>sodC<\/jats:italic>\n            \u0394\n            <jats:italic>sodA2<\/jats:italic>\n            ) 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\n            <jats:italic>sod15<\/jats:italic>\n            and\n            <jats:italic>sodA1<\/jats:italic>\n            to their wild-type state restored wild-type characteristics. We conclude that SOD molecules within the spore afford\n            <jats:italic>B. anthracis<\/jats:italic>\n            protection against oxidative stress and enhance the pathogenicity of\n            <jats:italic>B. anthracis<\/jats:italic>\n            in the lung. We also surmise that the presence of four SOD alleles within the genome provides functional redundancy for this key enzyme.\n          <\/jats:p>","DOI":"10.1128\/iai.00515-08","type":"journal-article","created":{"date-parts":[[2008,10,28]],"date-time":"2008-10-28T00:15:07Z","timestamp":1225152907000},"page":"274-285","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":100,"title":["Four Superoxide Dismutases Contribute to\n            <i>Bacillus anthracis<\/i>\n            Virulence and Provide Spores with Redundant Protection from Oxidative Stress"],"prefix":"10.1128","volume":"77","author":[{"suffix":"Jr.","given":"Robert J.","family":"Cybulski","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 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