T. Kielian et al., Diminished virulence of an alpha-toxin mutant of Staphylococcus aureus in experimental brain abscesses, INFEC IMMUN, 69(11), 2001, pp. 6902-6911
Staphylococcus aureus is one of the major etiologic agents of brain abscess
es in humans, occasionally leading to focal neurological deficits and even
death. The objective of the present study was to identify key virulence det
erminants 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-inactivat
ed S. aureus to induce proinflammatory cytokine or chemokine expression or
brain abscess formation in vivo. To directly address the contribution of vi
rulence determinants in brain abscess development, the abilities of S. aure
us strains with mutations in the global regulatory loci sarA and agr were e
xamined. 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 ex
pression of factors that are altered in the sarA agr double mutant. Evaluat
ion of an alpha-toxin mutant revealed a phenotype similar to that of the sa
rA agr mutant in vivo, as evidenced by lower bacterial burdens and attenuat
ion 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 su
rvival. Cells recovered from brain abscesses were shown to harbor S. aureus
intracellularly, providing a means by which the organism may establish chr
onic infections in the brain. Together, these data identify alpha-toxin as
a key virulence determinant for the survival of S. aureus in the brain.