Despite a considerable body of knowledge on the molecular basis of bacterial virulence mechanisms, little is known about bacterial infection dynamics at the single cell level, including in vivo survival and replication within individual host cells or spread between cells in infected tissue. Reporting in PLoS Biology, Sam Brown and colleagues combine microscopy and modelling techniques to explore the key variables that underlie the dynamics of Salmonella enterica infection of phagocytic cells.

Previous work by the authors, using microscopy and a mouse model of infection, showed that the growth of S. enterica in the tissues of infected animals resulted from the continuous spread of microorganisms to new phagocytic cells, rather than increased bacterial replication within the initially infected host cells. Indeed, each infected phagocyte typically had a low bacterial count that was independent of microbial growth rate or the duration of infection. This finding raised the possibility that the observed variation in intracellular bacterial counts was due to differences in the inherent host-cell response to S. enterica invasion and replication. To explore this possibility and to explain the observed intra- and intercellular infection dynamics, a simple mathematical model was developed. Results obtained using this model indicated that many host cells contained just one bacterium, whereas other cells contained several — a finding that mirrored the experimental microscopic observations. Furthermore, it was also shown that it is not necessary to invoke variation in the host-cell response to explain the differences in the number of microorganisms an infected phagocyte contains. The model was then used to investigate the origin of variability in host-cell response to infection, reaching the conclusion that stochastic rather than intrinsic differences between cells offered the best fit for the observational data.

Finally, using these insights into intra- and intercellular infection dynamics, the authors explored the effects of medical intervention. Using the model, the authors could demonstrate that inhibiting intracellular bacterial replication reduces the number of infective bacteria that trigger host-cell lysis and are released into the extracellular environment. In terms of therapy, an intriguing prediction from this analysis is that the efficacy of common extracellular antibiotics will be enhanced by the use of molecules that slow intracellular bacterial division.