Decomposing virulence: host, pathogen, and microbiota contributions

毒力描述了病原体对健康或适应能力的负面影响，长期以来，人们对了解毒力如何随着进化时间的变化而变化感兴趣。毒力将由病原体和宿主因素决定，但了解每个伴侣对毒力模式的影响程度并不是一件容易的事。然而，我们可以通过将毒力分解为病原体和宿主成分来开始了解毒力变化的驱动因素：病原菌通过a)利用，即其在宿主内复制的能力，以及b)对寄生虫的致病力，即它对每个病原体造成的损害量，对毒力做出贡献。寄主通过c)抗性(即抑制病原菌生长)和d)耐受性(即限制特定侵染量对健康的负面影响)来影响毒力。最近，人们对寄主、病原菌和微生物区系之间的三方相互作用以及微生物区系在病原菌毒力进化中所起的作用产生了浓厚的兴趣。在这项资助中，我们建议将毒力完全分解为所有四种寄主和病原体成分(a-d)，同时考虑到与微生物区系的相互作用。我们将使用实验进化的病原体，在存在和不存在的情况下产生一种角质层微生物区系，资助期间为5026。我们将首先测试祖先和两个进化的细菌病原体的毒力，1)微生物区系的存在和不存在，2A)寄主性别，3)不同的寄主种群。在每种情况下，我们将估计寄主和病原体成分(a-d)对这些毒力模式的贡献。为了揭示2A中毒力模式的潜在宿主驱动因素，在2B中，我们将分析雌性和雄性在系统感染祖先和进化的病原体时的转录反应。转录目标预计将补充毒力分解分析的推断，反之亦然。总体而言，这种方法意味着我们可以从寄主和病原体的角度在两个水平上同时评估影响：首先是广泛的毒力模式，然后是通过毒力分解更深入地了解进化变化。这个项目将深入了解毒力模式的普遍性，它将帮助我们发现毒力的隐藏驱动因素，它将深入了解毒力成分的普遍性。

Virulence describes the negative health or fitness effect of an pathogen, and there is long-standing interest in understanding how virulence changes over evolutionary time. Virulence will be determined by pathogen and host factors, but it is not trivial to understand the degree to which each partner affects virulence patterns. Nonetheless, we can start to understand the drivers of virulence changes by “decomposing” virulence into pathogen and host components: The pathogen contributes towards virulence through a) exploitation, that is its ability to replicate inside the host and b) per parasite pathogenicity, that is the amount of damage that it does per pathogen. The host affects virulence through c) resistance, that is suppression of pathogen growth and d) tolerance, that is limiting the negative health effects of a given infection load. More recently there has been a blossoming of interest in the tripartite interaction between host, pathogen and microbiota, and the role that microbiota play in pathogen virulence evolution. In this grant we propose to fully decompose virulence into all four host and pathogen components (a-d), whilst taking the interaction with microbiota into account. We will use pathogens experimentally evolved in the presence and absence of a species of cuticular microbiota resulting from funding period one of the Research Unit FOR 5026. We will first test the virulence of the ancestral and two evolved bacterial pathogens in the context of 1) the experimental presence and absence of microbiota, 2A) host sex, and 3) different host populations. In each case we will then estimate the contribution of the host and pathogen components (a-d) to these virulence patterns. To uncover potential host drivers of the virulence patterns in 2A, in 2B we will analyse the transcriptional responses of females and males upon systemic infection with the ancestral and evolved pathogens. The transcriptional objective is expected to compliment inferences from the virulence decomposition analysis, and vice versa. Overall, this approach means that we can simultaneously assess effects from the host and pathogen perspective on two levels: first broad-scale virulence patterns and subsequently a deeper understanding of evolutionary changes through a virulence decomposition. This project will give insight into the generalisability of virulence patterns, it will help us to uncover hidden drivers of virulence, and it will give insight into the generalisability of the components of virulence.