Comparative transcriptomics reveals <i>CrebA</i> as a novel regulator of infection tolerance in <i>D</i>. <i>melanogaster</i>

Host responses to infection encompass many processes in addition to activation of the immune system, including metabolic adaptations, stress responses, tissue repair, and other reactions. The response to bacterial infection in Drosophila melanogaster has been classically described in studies that focused on the immune response elicited by a small set of largely avirulent microbes. Thus, we have surprisingly limited knowledge of responses to infection that are outside the canonical immune response, of how the response to pathogenic infection differs from that to avirulent bacteria, or even of how generic the response to various microbes is and what regulates that core response. In this study, we addressed these questions by profiling the D. melanogaster transcriptomic response to 10 bacteria that span the spectrum of virulence. We found that each bacterium triggers a unique transcriptional response, with distinct genes making up to one third of the response elicited by highly virulent bacteria. We also identified a core set of 252 genes that are differentially expressed in response to the majority of bacteria tested. Among these, we determined that the transcription factor CrebA is a novel regulator of infection tolerance. Knock-down of CrebA significantly increased mortality from microbial infection without any concomitant change in bacterial number. Upon infection, CrebA is upregulated by both the Toll and Imd pathways in the fat body, where it is required to induce the expression of secretory pathway genes. Loss of CrebA during infection triggered endoplasmic reticulum (ER) stress and activated the unfolded protein response (UPR), which contributed to infection-induced mortality. Altogether, our study reveals essential features of the response to bacterial infection and elucidates the function of a novel regulator of infection tolerance.宿主对感染的应答涵盖了除免疫系统激活之外的诸多过程，包括代谢适应、应激反应、组织修复及其他反应。既往针对黑腹果蝇（Drosophila melanogaster）细菌感染应答的经典研究，多聚焦于少量大体为低毒的微生物所诱发的免疫反应。因此，我们对超出经典免疫应答范畴的感染应答、致病性感染与低毒细菌感染应答的差异，乃至不同微生物的感染应答具有多大程度的通用性、以及何种机制调控该核心应答的认知都极为有限。本研究通过分析黑腹果蝇对10种覆盖毒力谱系的细菌的转录组应答，解答了上述问题。研究发现，每种细菌均可触发独特的转录应答，对于高毒力细菌诱发的应答，独特基因占比可达三分之一。我们还鉴定出一套共252个基因的核心集，在受试的多数细菌感染后均会出现差异表达。其中，转录因子CrebA被确定为感染耐受性的新型调控因子。敲低CrebA会显著提升微生物感染后的死亡率，但不会伴随细菌数量的变化。感染后，脂肪体中的Toll通路与Imd通路均可上调CrebA的表达，而CrebA是诱导分泌通路基因表达所必需的。感染期间CrebA缺失会触发内质网（ER）应激并激活未折叠蛋白反应（UPR），该反应会加剧感染诱导的死亡率。综上，本研究揭示了细菌感染应答的关键特征，并阐明了感染耐受性新型调控因子的功能。