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What Can Genome-Wide Association Studies Tell Us about the Genetics of Common Disease?

Iles, M.M and Fisher, E.M.C (2008) What Can Genome-Wide Association Studies Tell Us about the Genetics of Common Disease? PLoS Genetics, 4 (2). e33. ISSN 1553-7404


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.

Item Type: Article
Copyright, Publisher and Additional Information: © 2008 Mark M. Iles. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institution: The University of Leeds
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 06 Nov 2009 12:43
Last Modified: 15 Sep 2014 04:08
Published Version: http://dx.doi.org/10.1371/journal.pgen.0040033
Status: Published
Publisher: Public Libary of Science
Identification Number: 10.1371/journal.pgen.0040033
URI: http://eprints.whiterose.ac.uk/id/eprint/10101

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