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Infection and Immunity, November 2001, p. 6902-6911, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6902-6911.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Diminished Virulence of an Alpha-Toxin Mutant of Staphylococcus aureus in Experimental Brain Abscesses

Tammy Kielian,1,* Ambrose Cheung,2 and William F. Hickey1

Departments of Pathology1 and Microbiology and Immunology,2 Dartmouth-Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire 03756

Received 23 March 2001/Returned for modification 8 June 2001/Accepted 23 July 2001

Staphylococcus aureus is one of the major etiologic agents of brain abscesses in humans, occasionally leading to focal neurological deficits and even death. The objective of the present study was to identify key virulence determinants contributing to the pathogenesis of S. aureus in the brain using a murine brain abscess model. The importance of virulence factor production in disease development was demonstrated by the inability of heat-inactivated S. aureus to induce proinflammatory cytokine or chemokine expression or brain abscess formation in vivo. To directly address the contribution of virulence determinants in brain abscess development, the abilities of S. aureus strains with mutations in the global regulatory loci sarA and agr were examined. An S. aureus sarA agr double mutant exhibited reduced virulence in vivo, as demonstrated by attenuated proinflammatory cytokine and chemokine expression and bacterial replication. Subsequent studies focused on the expression of factors that are altered in the sarA agr double mutant. Evaluation of an alpha-toxin mutant revealed a phenotype similar to that of the sarA agr mutant in vivo, as evidenced by lower bacterial burdens and attenuation of cytokine and chemokine expression in the brain. This suggested that alpha-toxin is a central virulence determinant in brain abscess development. Another virulence mechanism utilized by staphylococci is intracellular survival. Cells recovered from brain abscesses were shown to harbor S. aureus intracellularly, providing a means by which the organism may establish chronic infections in the brain. Together, these data identify alpha-toxin as a key virulence determinant for the survival of S. aureus in the brain.

* Corresponding author. Present address: University of Arkansas for Medical Sciences, Department of Anatomy and Neurobiology, B118 Biomedical Research Center, Slot 510, 4301 W. Markham St., Little Rock, AR 72205. Phone: (501) 526-6348. Fax: (501) 686-6382. E-mail: KielianTammyL{at}uams.edu.

Infection and Immunity, November 2001, p. 6902-6911, Vol. 69, No. 11
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.11.6902-6911.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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