Department of Mathematics, University of Glasgow, University Gardens, United Kingdom.
Am Nat. 2010 Oct;176(4):424-39. doi: 10.1086/656276.
Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, we introduce a mechanistic framework for modeling within-host infection dynamics. Our analysis focuses first on a single parasitemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. A major feature of trypanosome infections is the interaction between variant-specific host immunity and density-dependent parasite differentiation to transmission life stages. In this study, we investigate how the interplay between these two types of control depends on the modular structure of the parasite antigenic archive. Our model shows that the degree of synchronization in stochastic variant emergence determines the relative dominance of general over specific control within a single peak. A requirement for multiple-peak dynamics is a critical switch rate between blocks of antigenic variants, which implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics and provides insights into the evolution of trypanosomes.
病原体基因组数据的可用性不断增加，为理解慢性感染期间免疫逃避和病原体种群动态的基本机制提供了新的机会。受不断增长的关于昏睡病寄生虫（即非洲锥虫）抗原变异系统的知识的启发，我们引入了一个用于建模宿主内感染动力学的机制框架。我们的分析首先集中在单个寄生虫血症峰值上，然后研究依赖于寄生虫变异群之间随机切换的多个峰值的动态。锥虫感染的一个主要特征是变体特异性宿主免疫与密度依赖性寄生虫分化至传播生命阶段之间的相互作用。在这项研究中，我们研究了这两种类型的控制之间的相互作用如何取决于寄生虫抗原库的模块化结构。我们的模型表明，在随机变体出现的同步程度决定了在单个峰值中一般控制相对于特异性控制的相对优势。多峰动力学的一个要求是抗原变体块之间的临界开关率，这意味着对变异表面糖蛋白（VSG）库遗传多样化的限制。我们的研究说明了量化寄生虫遗传学与宿主内动力学之间联系的重要性，并为锥虫的进化提供了新的见解。
