Intracellular demography and the dynamics of Salmonella enterica infections.
An understanding of within-host dynamics of pathogen interactions with eukaryotic cells can shape the development of effective preventive measures and drug regimes. Such investigations have been hampered by the difficulty of identifying and observing directly, within live tissues, the multiple key variables that underlay infection processes. Fluorescence microscopy data on intracellular distributions of Salmonella enterica serovar Typhimurium (S. Typhimurium) show that, while the number of infected cells increases with time, the distribution of bacteria between cells is stationary (though highly skewed). Here, we report a simple model framework for the intensity of intracellular infection that links the quasi-stationary distribution of bacteria to bacterial and cellular demography. This enables us to reject the hypothesis that the skewed distribution is generated by intrinsic cellular heterogeneities, and to derive specific predictions on the within-cell dynamics of Salmonella division and host-cell lysis. For within-cell pathogens in general, we show that within-cell dynamics have implications across pathogen dynamics, evolution, and control, and we develop novel generic guidelines for the design of antibacterial combination therapies and the management of antibiotic resistance.
Brown
Sam P
SP
Department of Zoology, University of Cambridge, Cambridge, United Kingdom. sam.brown@cantab.net
Cornell
Stephen J
SJ
Sheppard
Mark
M
Grant
Andrew J
AJ
Maskell
Duncan J
DJ
Grenfell
Bryan T
BT
Mastroeni
Pietro
P
D000818:Animals; D002451:Cell Compartmentation; D003593:Cytoplasm / Q000382:microbiology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D008954:Models, Biological; D015388:Organelles / Q000382:microbiology; D012480:Salmonella Infections / Q000188:drug therapy / Q000473:pathology*; D012481:Salmonella Infections, Animal / Q000188:drug therapy; D019779:Salmonella enterica / Q000187:drug effects; D013269:Stochastic Processes