Decomposing virulence: host, pathogen, and microbiota contributions

毒力描述了病原体对健康或适应性的负面影响，人们长期以来一直有兴趣了解毒力如何随着进化时间而变化。毒力将由病原体和宿主因素决定，但了解每个伴侣影响毒力模式的程度并非易事。尽管如此，我们可以通过将毒力“分解”为病原体和宿主成分来开始理解毒力变化的驱动因素：病原体通过a）利用（即其在宿主内复制的能力）和B）每个寄生虫的致病性（即其对每个病原体造成的损害量）来贡献毒力。宿主通过c）抗性（即抑制病原体生长）和d）耐受性（即限制给定感染负荷的负面健康影响）影响毒力。最近，人们对宿主、病原体和微生物群之间的三方相互作用以及微生物群在病原体毒力进化中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宿主和病原体组分（a-d），同时考虑与微生物群的相互作用。我们将使用在存在和不存在一种表皮微生物群的情况下实验进化的病原体，这些微生物群来自5026研究单位的第一个资助期。我们将首先在1）实验存在和不存在微生物群，2A）宿主性别和3）不同宿主种群的背景下测试祖先和两种进化细菌病原体的毒力。在每种情况下，我们将估计宿主和病原体组分（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全身感染祖先和进化病原体后的转录反应。预期转录目标将补充毒力分解分析的推断，反之亦然。总的来说，这种方法意味着我们可以同时从宿主和病原体的角度在两个层面上评估影响：首先是大规模的毒力模式，随后通过毒力分解更深入地了解进化变化。该项目将深入了解毒力模式的普遍性，它将帮助我们发现隐藏的毒力驱动因素，并将深入了解毒力组成部分的普遍性。

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.