Data from: The genetic architecture of defense as resistance to and tolerance of bacterial infection in Drosophila melanogaster

Defense 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. 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 coevolutionary 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. In order to understand the impact of tolerance on host defense and identify genetic variants that determine host tolerance, we defined a novel measure of genetic variation in tolerance. We then performed a genome-wide association study (GWAS) to map the genetic basis for variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and relative tolerance and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that alter 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 defense, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defense arises from a collection of physiological processes intertwined with canonical immunity and resistance.

宿主对抗病原体感染的防御策略可分为两类：抗性（resistance）与耐受（tolerance）。抗性指宿主限制病原体载量的能力，而耐受则是宿主抑制感染所引发负面后果的能力。从进化视角来看，一种独立于抗性的耐受策略可使宿主避免触发代价高昂的免疫应答，理论上还能规避病原体毒力与宿主抗性之间的协同进化军备竞赛。从生物医学角度而言，阐明耐受的作用机制及其与抗性的关联，有望催生以改善宿主健康而非清除病原体为核心目标的治疗策略。为明确耐受对宿主防御的影响并筛选调控宿主耐受的遗传变异（genetic variants），我们定义了一种全新的耐受相关遗传变异量化指标。随后，我们针对雷氏普罗威登斯菌（Providencia rettgeri）感染的抗性与耐受差异开展全基因组关联研究（genome-wide association study, GWAS），以解析其遗传基础。研究发现，抗性与相对耐受之间存在正向遗传相关，且证实抗性水平可高度预测耐受水平。我们共鉴定出30个可调控耐受的基因座（loci），其中多数位于参与免疫与代谢调控的基因内部。我们借助RNA干扰（RNA interference, RNAi）技术验证，部分定位到的基因参与宿主防御过程，其中包括潜在伤口修复基因grainy head与debris buster。本研究结果表明，耐受并非独立于抗性的防御策略，宿主防御实则是一系列与经典免疫及抗性相互交织的生理过程共同介导的结果。