The evolutionary dynamics of drug resistance in host-pathogen interactions

传染病仍然是对人类健康的最重大威胁之一。已经开发了许多药物干预措施（例如抗生素和其他化疗药物）来减缓或阻止疾病的传播，但现在非常清楚的是，病原体的进化往往使这些工具无效。这个问题的核心是进化生物学中更基本的问题，即对新的选择因子产生最大进化反应的条件。事实上，这个问题也是许多其他重要应用问题的核心，从优化蛋白质和酶工程的定向进化方法，到了解物种何时适应气候变化而不是灭绝。拟议的研究在耐药性的背景下解决了这一重要问题。我们将发展数学理论来预测不同药物干预的进化后果，并解决三个主要问题：(1)哪些因素使使用高浓度和低浓度的药物来最好地控制耐药性？(2)时空变异对抗性的产生有何影响？(3)能否操纵生态相互作用使种群免于进化？作为培训的一部分，我的学生还将与一位研究疟疾小鼠模型系统的同事合作，对该理论的某些方面进行实验测试。从长远来看，我们的希望是，这项研究将为卫生保健科学家开展更多临床导向的研究奠定基础。

Infectious diseases remain one of the most significant threats to human health. Many pharmaceutical interventions (e.g., antibiotics and other chemotherapeutic agents) have been developed to slow or stop the spread of disease, but it is now abundantly clear that pathogen evolution often renders these tools ineffective. At the center of this issue is the more fundamental question in evolutionary biology of the conditions that generate the greatest evolutionary response to novel selective agents. Indeed this question also lies at the heart of many other important applied problems, from the optimization of directed evolution approaches for protein and enzyme engineering, to understanding when species will adapt to climate change as opposed to going extinct. The proposed research addresses this important issue in the context of drug resistance. We will develop mathematical theory to predict the evolutionary consequences of different drug interventions, and address three main questions:(1) What factors make it optimal to use high versus low drug concentrations to best control resistance?(2) What role does temporal and spatial variation play in the emergence of resistance?(3) Can we manipulate ecological interactions to make populations evolution-proof?As part of training, my students will also conduct experimental tests of some aspects of the theory, in collaboration with a colleague who works with a mouse model system of malaria. In the longer-term our hope is that this research will lay the fundamental foundations for more clinically oriented studies carried out by health-care scientists.