Modeling the Spatial Dynamics of Plasmid Transfer

描述(申请人提供)：质粒在细菌之间的抗生素耐药性传播中起着核心作用，从而降低了各种化疗药物治疗传染病的有效性。这些可移动的遗传元件在细菌中非常常见，它们的水平转移是这些生物适应性进化的关键。这项研究的长期目标是了解空间结构微生物群落中可传播质粒的种群生物学：驱动这些可移动遗传元件的水平转移和持久性的机制是什么？为什么它们会坚持下来，即使它们携带的任何基因都没有被选择呢？自然微生物群落的空间结构如何影响质粒-细菌相互作用的生态和进化动态？因此，我们建议对空间结构在自传抗生素耐药质粒的传播和持久性中的作用进行联合的理论和实验研究。该方案的具体目标是构建2维和3维随机细胞自动机(CA)模型，该模型可以用于准确预测天然抗生素耐药质粒在琼脂表面和生物膜上生长的细菌菌落中的传播和持久性。这两个设置对于仔细控制与非空间(液体)环境的比较和空间相关参数的估计以及了解生物膜复杂的空间异质结构进一步影响质粒转移和持久性的程度是必要的。为了验证和/或修改模型，将进行一系列平行的体外和电子实验。每一对这样的实验将用于：(A)验证或拒绝与特定生物假说相关的特定模型；(B)建议模型改进；(C)检验生物假说；以及(D)在原始假说被拒绝的情况下制定替代假说。

DESCRIPTION (provided by applicant): Plasmids play a central role in the spread of antibiotic resistance among bacterial species, thereby decreasing the effectiveness of various chemotherapeutic agents for the treatment of infectious diseases. These mobile genetic elements are very common in bacteria and their horizontal transfer is key in the adaptive evolution of these organisms. The long-term goal of this study is to understand the population biology of transmissible plasmids in spatially structured microbial communities: What are the mechanisms that drive the horizontal transfer and persistence of these mobile genetic elements? Why do they persist, even in the absence of selection for any of the genes they carry? How does the spatial structure of natural microbial communities influence the ecological and evolutionary dynamics of plasmid-bacteria interactions? Therefore, a joint theoretical and experimental investigation into the role of spatial structure in the spread and persistence of self-transmissible antibiotic resistance plasmids is proposed. The specific aims of this proposal are to construct 2-dimensional and 3-dimensional stochastic cellular automata (CA) models that can be used to accurately predict the spread and persistence of natural antibiotic resistance plasmids in bacterial colonies growing on agar surfaces and in biofilms. These two settings are needed for carefully controlled comparisons with non-spatial (liquid) environments and estimation of spatially relevant parameters, and for understanding the extent to which the complex spatially heterogeneous structure of biofilms further influences plasmid transfer and persistence. To validate and/or modify the models, a sequence of parallel in vitro and in silico experiments will be performed. Each such pair of experiments will serve to (a) validate or reject the particular model as pertains to a specific biological hypothesis; (b) suggest model refinements; (c) test the biological hypothesis; and (d) formulate alternative hypotheses in the event that the original hypothesis is rejected.