Within-Host Stochastic Emergence Dynamics of Immune-Escape Mutants

Predicting the emergence of new pathogenic strains is a key goal of evolutionary epidemiology. However, the majority of existing studies have focussed on emergence at the population level, and not within a host. In particular, the coexistence of pre-existing and mutated strains triggers a heightened immune response due to the larger total pathogen population; this feedback can smother mutated strains before they reach an ample size and establish. Here, we extend previous work for measuring emergence probabilities in non-equilibrium populations, to within-host models of acute infections. We create a mathematical model to investigate the emergence probability of a fitter strain if it mutates from a self-limiting strain that is guaranteed to go extinct in the long-term. We show that ongoing immune cell proliferation during the initial stages of infection causes a drastic reduction in the probability of emergence of mutated strains; we further outline how this effect can be accurately measured. Further analysis of the model shows that, in the short-term, mutant strains that enlarge their replication rate due to evolving an increased growth rate are more favoured than strains that suffer a lower immune-mediated death rate (‘immune tolerance’), as the latter does not completely evade ongoing immune proliferation due to inter-parasitic competition. We end by discussing the model in relation to within-host evolution of human pathogens (including HIV, hepatitis C virus, and cancer), and how ongoing immune growth can affect their evolutionary dynamics.预测新型致病菌株的出现是进化流行病学（evolutionary epidemiology）的核心研究目标之一。然而，当前绝大多数相关研究均聚焦于种群层面的菌株出现事件，而非宿主内的菌株演化过程。具体而言，预存菌株与突变菌株的共存会因病原体总载量升高而触发更强的免疫应答；这种反馈机制可在突变菌株达到足够种群规模并成功定植前，抑制其增殖与扩散。 在此基础上，我们将此前针对非平衡种群的菌株出现概率测算方法，拓展至急性感染的宿主内模型中。我们构建了一套数学模型，用于探究适配性更强的突变菌株的出现概率——该突变菌株由一种自限性（self-limiting）菌株突变而来，而该自限性菌株最终必然走向灭绝。 研究发现，感染初始阶段持续发生的免疫细胞增殖，会大幅降低突变菌株的出现概率；我们还进一步阐明了如何精准量化这一效应。 对模型的深入分析还表明，短期内，通过提升生长速率以提高复制速率的突变菌株，相较于那些免疫介导死亡率更低（即‘免疫耐受’）的菌株更具演化优势：这是因为后者无法通过病原体间的竞争完全规避持续的免疫清除作用。 最后，我们将结合人类病原体（包括人类免疫缺陷病毒（HIV）、丙型肝炎病毒（hepatitis C virus）以及致癌病原体）的宿主内演化过程，探讨该模型的应用场景，并分析持续的免疫增殖如何影响这些病原体的演化动力学。