Brown Sam P, Cornell Stephen J, Sheppard Mark, Grant Andrew J, Maskell Duncan J, Grenfell Bryan T, Mastroeni Pietro
Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
PLoS Biol. 2006 Oct;4(11):e349. doi: 10.1371/journal.pbio.0040349.
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.
了解病原体与真核细胞在宿主体内的相互作用动态，有助于制定有效的预防措施和药物治疗方案。然而，由于难以在活组织中直接识别和观察到感染过程背后的多个关键变量，此类研究受到了阻碍。关于鼠伤寒沙门氏菌（S. Typhimurium）细胞内分布的荧光显微镜数据表明，虽然感染细胞的数量随时间增加，但细胞间细菌的分布是稳定的（尽管高度不均）。在此，我们报告了一个关于细胞内感染强度的简单模型框架，该框架将细菌的准稳定分布与细菌和细胞的种群统计学联系起来。这使我们能够否定偏态分布是由内在细胞异质性产生的假设，并得出关于沙门氏菌分裂和宿主细胞裂解的细胞内动态的具体预测。对于一般的细胞内病原体，我们表明细胞内动态对病原体动态、进化和控制具有影响，并为抗菌联合疗法的设计和抗生素耐药性的管理制定了新的通用指导原则。
