Evolutionary emergence of infectious diseases in heterogeneous host populations

The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence. Yet, the ecological factors that govern such evolutionary emergence remain elusive because of the lack of ecological realism of current theoretical frameworks and the difficulty of experimentally testing their predictions. Here, we develop a theoretical model to explore the effects of the heterogeneity of the host population on the probability of pathogen emergence, with or without pathogen evolution. We show that evolutionary emergence and the spread of escape mutations in the pathogen population is more likely to occur when the host population contains an intermediate proportion of resistant hosts. We also show that the probability of pathogen emergence rapidly declines with the diversity of resistance in the host population. Experimental tests using lytic bacteriophages infecting their bacterial hosts containing Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated (CRISPR-Cas) immune defenses confirm these theoretical predictions. These results suggest effective strategies for cross-species spillover and for the management of emerging infectious diseases.

病原体的新发与再现始终是公共卫生领域的重大关切。令人遗憾的是，由于传染病早期阶段病原体进化的随机性进一步加剧了此类事件的不可预测性，因此病原体（再）出现的时间与地点向来难以精准预判。例如，能使病原体逃逸宿主免疫抗性的突变，可增强病原体传播能力并推动其新发。然而，由于当前理论框架缺乏生态学真实性，且其实证预测难以通过实验验证，因此调控此类进化性新发的生态因子仍尚不明确。本研究构建了一套理论模型，用以探讨宿主种群异质性对病原体新发概率的影响，无论病原体是否发生进化。研究表明，当宿主种群中抗性宿主占比处于中等水平时，病原体进化性新发以及逃逸突变在病原体种群中的传播更易发生。同时还发现，病原体新发概率会随宿主种群抗性多样性的提升而快速下降。本研究利用裂解性噬菌体感染携带成簇规律间隔短回文重复序列及CRISPR相关蛋白（Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated, CRISPR-Cas）免疫防御系统的细菌宿主开展实验验证，结果证实了上述理论预测。上述研究结果为跨物种溢出事件防控以及新发传染病的管理提供了可行策略。