Heterogeneity of intracellular replication of bacterial pathogens.

Intracellular growth of bacterial pathogens is usually measured at the whole population level, which masks potential cell-to-cell variation. More direct measurements of replication using microscopy and Flow Cytometry have revealed extensive heterogeneity among populations of intracellular bacteria. Heterogeneity could result from differential exposure to nutritional deprivation and host cell antimicrobial activities, as well as variability in production or efficacy of virulence molecules. Furthermore, bacteria have evolved specific mechanisms to generate epigenetic variation. These include unequal partitioning of proteins during cell division, genetic phase variation and activation of toxin/antitoxin systems. An important aspect of heterogeneity concerns the generation of viable, non-replicating bacteria. These are predicted to confer tolerance to host-induced stress and antibiotics, and to be sources of persistent infection.