Howick Virginia M, Lazzaro Brian P
Department of Entomology, Cornell Institute of Host-Microbe Interactions and Disease, Cornell University, Comstock Hall, Ithaca, NY, 14853, USA.
Mol Ecol. 2017 Mar;26(6):1533-1546. doi: 10.1111/mec.14017. Epub 2017 Feb 16.
Defence against pathogenic infection can take two forms: resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, whereas tolerance is the ability to limit the negative consequences of infection at a given level of infection intensity. Evolutionarily, a tolerance strategy that is independent of resistance could allow the host to avoid mounting a costly immune response and, theoretically, to avoid a co-evolutionary arms race between pathogen virulence and host resistance. Biomedically, understanding the mechanisms of tolerance and how they relate to resistance could potentially yield treatment strategies that focus on health improvement instead of pathogen elimination. To understand the impact of tolerance on host defence and identify genetic variants that determine host tolerance, we defined genetic variation in tolerance as the residual deviation from a binomial regression of fitness under infection against infection intensity. We then performed a genomewide association study to map the genetic basis of variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and tolerance, and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that predict tolerance, many of which are in genes involved in the regulation of immunity and metabolism. We used RNAi to confirm that a subset of mapped genes have a role in defence, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defence arises from a collection of physiological processes intertwined with canonical immunity and resistance.
抗性和耐受性。抗性是宿主限制病原体负荷的能力，而耐受性是在给定感染强度水平下限制感染负面后果的能力。从进化角度来看，一种独立于抗性的耐受性策略可以使宿主避免产生代价高昂的免疫反应，并且从理论上讲，可以避免病原体毒力与宿主抗性之间的共同进化军备竞赛。在生物医学方面，了解耐受性机制以及它们与抗性的关系可能会产生侧重于改善健康而非消除病原体的治疗策略。为了了解耐受性对宿主防御的影响并确定决定宿主耐受性的基因变异，我们将耐受性的基因变异定义为感染条件下适应性的二项式回归相对于感染强度的残差偏差。然后，我们进行了全基因组关联研究，以绘制对雷氏普罗威登斯菌感染的抗性和耐受性变异的遗传基础。我们发现抗性和耐受性之间存在正遗传相关性，并且证明抗性水平高度预测耐受性。我们鉴定出30个预测耐受性的基因座，其中许多位于参与免疫和代谢调节的基因中。我们使用RNA干扰来证实一部分定位基因在防御中起作用，包括假定的伤口修复基因颗粒头和碎片清除蛋白。我们的结果表明，耐受性不是一种独立于抗性的策略，而是防御来自与经典免疫和抗性交织在一起的一系列生理过程。
