Discrete and Continuum Multiscale Behaviour in Bacterial Communication - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 295

emitted would not merit the energy expended on generating the bioluminescence,
meaning that this phenotype should be induced only at high population density.
This understanding between the cells is mediated by extracellular signal molecules
and the process has been termed 'quorum sensing' (the behaviour of the bacteria
alters once a quorum has been attained). Cell communication is now known to be
prevalent throughout the bacterial kingdom [ 5 , 28 ].
Though signalling pathways vary between species (most notably between
Gram-positive and Gram-negative bacteria) the phenomenon generally consists of
the production of diffusible signal molecules and their excretion into the envi-
ronment, allowing detection by other cells. The level of signal molecules in the
environment is a reflection of the population size or density, and the number of
signal molecules detected by an individual cell will determine the regulatory gene
cascade which is triggered and ultimately the behaviour of the cell. A sufficiently
well-mixed population should therefore act in a synchronised manner.
Since its discovery in the form of bioluminescence, quorum sensing has been
found to regulate a spectrum of bacterial behaviours, many of which, such as
biofilm formation, virulence, sporulation and swarming motility [ 5 , 28 ], are
medically significant. Biofilm formation in particular causes huge problems on
medical implant devices such as catheters. Modelling quorum sensing in biofilms
poses additional complications since, unlike the relatively homogeneous popula-
tions that occur in other contexts, biofilms are highly heterogeneous, comprising
layers of mixed populations of cells with quorum-sensing signal production (and
therefore cell phenotype) varying throughout the biofilm. Spatial variation is
something on which we focus in the models presented later, albeit in contexts
much simpler than those arising in biofilms.
The goal of quorum sensing is often to coordinate a particular behaviour which
would be futile were the whole population not engaged. For instance, it is believed
that Staphylococcus aureus switches on the production of virulence factors,
thereby attacking the host, only when it is present in sufficient numbers to over-
whelm the resulting immune response [ 25 ]. Thus the population should act in a
concerted fashion. In other contexts, however, quorum sensing may not be regu-
lating the response of a large population. Since signal molecule build-up can arise
as a result of a confined environment, rather than a large population, quorum
sensing can also serve to detect environmental conditions (this is sometimes
referred to as diffusion sensing [ 23 ]). For instance, the same quorum-sensing
system in S. aureus (i.e. the agr operon) is thought also to trigger endosome escape
[ 22 ] (only one or two cells are contained within a host cell), whereby signal
aggregation determines the escape time.
We have also recently used a mathematical model of quorum sensing by
Clostridium acetobutylicum (which uses a modified agr operon) [ 10 ] to illustrate
that, if the quorum-sensing system is composed of fewer feedback loops (thus
softening the response), it is possible that it can be used to anticipate hostile
environments and, rather than coordinating behaviour at the whole population
level, send only a portion of cells to a sporulation fate (making them capable of
surviving these conditions). By maintaining a number in a vegetative state, the