The regulation of toxin production in Staphylococcus aureus.

Staphylococcus aureus
is a major human pathogen causing a wide range of
illnesses
from the trivial to the
life-threatening. S. aureus produces many surface-associated
and exoproteins, several of which have been implicated in its virulence. Production
of these virulence determinants is co-ordinately controlled by several global
regulatory elements
in a growth phase
dependent manner. The best characterised of
these regulators are the accessory gene regulator
(agr) and staphylococcal accessory
regulator
(sar). The agr
locus comprises a quorum sensing system and encodes a
signalling pheromone that autoregulates agr
in a density dependent manner.
Upregulation of agr expression
leads to production of an mRNA transcript, RNAHI
which
is
the actual effector of virulence gene expression. The RNAIII molecule
upregulates several extracellular toxins
including haemolysins, toxic shock syndrome
toxin 1 (TSST-1) and epidermolytic
toxin A (Eta), and down-regulates surface
proteins such as protein A and
fibronectin binding protein
(FnBP) during late
exponential growth and stationary phase.
The
regulation of toxin production by S. aureus
is extremely complex and
it is not yet
understood exactly how this organism responds to environmental stimuli
in order to
mediate changes
in
virulence gene expression.
In order to determine whether
environmental signals are transduced via agr, the effect of several stimuli on both agr
expression and a-haemolysin production was examined using a ß-galactosidase
reporter gene
fusion
to the hid gene, which
is encoded as part of the RNAIII
transcript. A number of environmental stimuli were
identified which
led to changes
in
agr expression. Several of these stimuli resulted
in different effects on a-
haemolysin activity when compared to RNAIII levels. This suggests the presence of
novel regulatory elements
involved in the control of Hla production,
independently of
agr. In order to
identify other novel regulators which
interact with, or control, agr,
transposon
libraries have been created using Tn917 and Tn551. Two Tn917
transposon mutants were
isolated as deficient in production of ß-haemolysin, which
is
also positively controlled by agr. These mutants were
found to contain novel
transposon
insertions in
the agr
locus. Five Tn551 mutants were
isolated which
showed pleiotropic effects on virulence determinant levels and did not contain the
transposon in previously mapped regulators. The Tn551 insertions may have
therefore occurred
in novel regulators of virulence determinant production.
The
regulation of toxin production by S. aureus
in
response to environmental stimuli
is discussed.