Comparative transcriptomics reveals CrebA as a novel regulator of infection tolerance in D. melanogaster.
Comparative transcriptomics reveals CrebA as a novel regulator of infection tolerance in D. melanogaster.
复制标题
DOI：
10.1371/journal.ppat.1006847
复制
发表时间：
2018-03
期刊：
影响因子：
6.7
通讯作者：
Buchon N
中科院分区：
文献类型：
--
作者：
Troha K;Im JH;Revah J;Lazzaro BP;Buchon N
宿主对感染的反应除了激活免疫系统外还包括许多过程，包括代谢适应、应激反应、组织修复和其他反应。果蝇对细菌感染的反应已经在研究中经典地描述，这些研究集中于由一小部分无毒微生物引起的免疫反应。因此，我们对典型免疫反应之外的感染反应，对病原性感染的反应与无毒细菌的反应有何不同，甚至对各种微生物的反应有多普遍以及是什么调节了核心反应，都知之甚少。在这项研究中，我们解决了这些问题，通过分析D。黑腹菌转录组对10种细菌的反应跨越毒力谱。我们发现，每种细菌都会触发一种独特的转录反应，不同的基因占高毒性细菌引发的反应的三分之一。我们还确定了一组核心的252个基因，这些基因在大多数测试的细菌中差异表达。其中，我们确定了转录因子CrebA是一种新的感染耐受性调节因子。敲低CrebA显著增加了微生物感染的死亡率，而细菌数量没有任何伴随变化。在感染后，CrebA通过脂肪体中的Toll和Imd途径上调，其中需要CrebA来诱导分泌途径基因的表达。感染过程中CrebA的丢失触发内质网（ER）应激并激活未折叠蛋白反应（UPR），这导致感染诱导的死亡率。总之，我们的研究揭示了细菌感染反应的基本特征，并阐明了一种新的感染耐受调节剂的功能。生物体如何在感染后存活？宿主对不同病原体的反应有多普遍或特异？为了解决这些问题，我们用10种不同的细菌感染果蝇，这些细菌杀死果蝇的能力各不相同，并测量了全球基因表达的变化。总的来说，我们发现宿主反应对单个细菌具有高度特异性。然而，我们还发现了一组基因，这些基因在对大多数测试细菌的反应中改变了表达。在这些基因中，我们确定了转录因子CrebA是一种新的调节宿主对感染的反应。我们发现，感染后，免疫系统诱导CrebA的表达。CrebA缺陷型果蝇更容易死于感染，尽管它们携带的细菌数量与野生型果蝇相同。CrebA在脂肪体（一种类似于哺乳动物肝脏和脂肪组织的器官）中表达，在脂肪体中它调节多个分泌途径基因的转录。感染期间CrebA的丢失触发内质网（ER）应激（一种细胞应激），这足以使苍蝇对感染敏感。这些结果表明，免疫系统可以调节宿主生理机能，以防止感染相关细胞应激的有害影响。
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. How does an organism survive infection? How generic or specific is the host response to diverse pathogens? To address these questions, we infected fruit flies with 10 different bacteria that vary in their ability to kill flies and measured changes in global gene expression. In general, we found that the host response is highly specific to individual bacteria. However, we also discovered a set of genes that changed expression in response to the majority of bacteria tested. Among these genes, we determined that the transcription factor CrebA is a novel regulator of the host response to infection. We found that upon infection, the immune system induces the expression of CrebA. CrebA-deficient flies are more likely to die from infection despite carrying the same number of bacteria as wildtype flies. CrebA is expressed in the fat body, an organ analogous to the mammalian liver and adipose tissues, where it regulates the transcription of multiple secretory pathway genes. Loss of CrebA during infection triggers endoplasmic reticulum (ER) stress (a type of cellular stress), which is sufficient to sensitize flies to infection. These results suggest that the immune system can modulate host physiology to prevent the deleterious effect of infection-associated cellular stress.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9
作者：
Demay Y;Perochon J;Szuplewski S;Mignotte B;Gaumer S
通讯作者：
Gaumer S
影响因子：
9.2
作者：
Clark, Rebecca I.;Woodcock, Katie J.;Geissmann, Frederic;Trouillet, Celine;Dionne, Marc S.
通讯作者：
Dionne, Marc S.
DOI：
10.1111/tra.12038
发表时间：
2013-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Barbosa S;Fasanella G;Carreira S;Llarena M;Fox R;Barreca C;Andrew D;O'Hare P
通讯作者：
O'Hare P
影响因子：
7.7
作者：
Duneau D;Ferdy JB;Revah J;Kondolf H;Ortiz GA;Lazzaro BP;Buchon N
通讯作者：
Buchon N