Abstract: Salmonella enterica serovar Typhimurium invades the intestinal
epithelial cells using type three secretion system (TTSS) encoded on Salmonella
pathogenicity island-1 (SPI-1). The key regulator of this secretion system is
HilA, which is in turn regulated by HilD, HilC and RtsA. It is also known that
SirA/BarA system, a two-component regulatory system plays a crucial role in
regulating HilA. There are two different mechanisms that have been proposed earlier
for regulation of HilD-HilC-RtsA-HilA network by SirA. One considers SirA to be
acting through HilA and HilC, whereas the other considers SirA to be acting
through HilD. In this paper, we have built mathematical models corresponding to
both these scenarios and carried out simulations under different gene knock-out
conditions. Additionally, since the two proposed mechanisms based on the
experimental data are equally likely, we also considered a mechanism which is a
combination of the two proposed mechanisms. The simulations were carried out to
check the levels of HilA, the factor regulating the virulence, as well as the
levels of the intermediate components in the network, namely HilC and RtsA. The
simulation results were used to check the consistency of various models and
also to suggest the most probable mechanism of hilA regulation. The results of our study show that while most of the mathematical
models are able to predict the virulence data, the models considering SirA to
regulate through HilA and HilC fail to predict the levels of intermediate
components, HilC and RtsA. Nevertheless, one of the models considering
regulation of virulence by SirA via HilD was able to predict results comparable
to the experimental data. In addition, combination of this model (regulation by
SirA via HilD) with the model considering regulation by SirA through HilA and
HilC, also predicted results consistent with experimental observations. Our
conclusions were further validated by testing the stability of the results
against changes in parameter values, thus confirming the relative robustness of
the proposed modeling system.
Keywords: Salmonella, pathogenicity, type three secretion system, virulence, HilA, SirA, mathematical modeling
