The Staphylococcus aureus secretome - TI Pharma

Chapter 4
aureus lgt mutants may be hypervirulent in vivo (Stoll et al., 2005;Bubeck et al., 2006), which
would be in line with our present findings. The observation that the srtB mutant is attenuated
in C. elegans killing suggests that the IsdC protein is required for C. elegans killing and that
S. aureus cells are exposed to iron-limiting conditions during C. elegans infection
(Mazmanian et al., 2003). This would in fact suggest that the reason why the lspA mutant is
attenuated might be related to the malfunction of certain lipoproteins involved in iron uptake
(Schmaler et al., 2009). Remarkably, the tatAC mutant showed a higher killing rate compared
to the parental strain. This finding is somewhat difficult to reconcile with the observed C.
elegans killing phenotypes of the srtB and lspA mutants, because the only confirmed substrate
for the S. aureus Tat pathway is the FepB protein, which is an iron-dependent peroxidase
needed for iron uptake (Biswas et al., 2009). Moreover, the bacterial loads of tatAC and tatfep
mutant strains in a mouse kidney abscess model were decreased, suggesting a requirement
of the Tat pathway for virulence. At present, it remains unfortunately unclear why the effects
of the srtB and lspA mutations on the one hand and the tatAC mutation on the other hand are
so different. Finally, it is important to note that no C. elegans killing phenotype was observed
for the srtA mutant. Clearly, the proteins anchored by sortase A to the cell surface are very
important for the virulence of S. aureus towards mammals as they are, for example, involved
in the binding of fibrinogen (McDevitt et al., 1997), binding to nasal epithelial cells (Corrigan
et al., 2009), evasion of the immune system (Sasso et al., 1991) or biofilm formation
(Corrigan et al., 2007). Possibly, these traits are less relevant for S. aureus virulence towards
much simpler host organisms such as nematodes.
Outlook
In conclusion, our present studies show that many of the non-essential determinants for
protein secretion by S. aureus have only a limited impact on general protein secretion by this
organism. This implies that these factors are mainly required for special purposes that may,
however, be relevant for the virulence of S. aureus. Defining the precise roles of such
secretion factors will require more in-depth studies, especially under infection mimicking
conditions. An important lesson that was learned from the studies with the S. aureus strain
SH1000 is that this strain quite rapidly accumulates mutations causing an agr-like phenotype.
This underscores the need for genetically stable model strains for molecular genetics and
proteomics approaches to fully define the roles of the secretome in staphylococcal virulence.
Acknowledgements
We like to thank W. Baas for technical assistance, and colleagues from the StaphDynamics
and TIPharma programs for helpful discussions. Financial support was provided by CEU
(StaphDynamics, LSHM-CT-2006-019064; DFG (GK212/3-00, SFB/TR34, FOR 585), and
Top Institute Pharma (T4-213).
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