Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions.
Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions.
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DOI：
10.3389/fmicb.2022.853629
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发表时间：
2022
影响因子：
5.2
通讯作者：
Benedetto, Alexandre
中科院分区：
文献类型：
--
作者：
Zarate-Potes, Alejandra;Ali, Irtiqa;Camacho, Margarida Ribeiro;Brownless, Hayley;Benedetto, Alexandre
由于缺乏有效的可持续干预措施，控制线虫引起的影响全世界牛和作物的疾病仍然是一个关键的经济问题。蛔虫与其环境微生物（包括其微生物群）的相互依赖性为制定更具针对性的驱虫策略提供了机会。然而，信息的匮乏和目前狭隘的理解，线虫-微生物相互作用限于特定的感染contextual. With组学方法来映射宿主-微生物的遗传相互作用，特别是在模型线虫的出现，大数据集，现在可以在多个模型，使识别线虫-微生物的特定途径。在这项工作中，我们收集了20个转录组数据集记录基因表达变化的C。线虫暴露于20种不同的真菌和病原微生物，进行基因富集分析，然后使用针对感兴趣基因的RNA干扰进行功能测试，然后对比转录组学荟萃分析和表型组学的结果。差异表达分析揭示了信号传导、先天免疫应答和（脂质）代谢基因的广泛富集。在信号转导基因家族中，线虫趋异和扩展的刺猬样信号转导（HHLS）途径的特点突出。事实上，24/60 C。线虫刺猬样蛋白（Hedgehog-like proteins，HRPs）和15/27的Patched-related receptor（PTRs）在至少四种微生物环境中差异表达，而高达32/60的HRPs在单一环境中差异表达。有趣的是，差异表达的基因遵循微生物特异性模式，提示适应性微生物特异性反应。为了进一步研究这一点，我们通过RNAi敲低了96个单独的HHLS基因，使用高通量测定来评估它们对三种蠕虫肠道感染模型（铜绿假单胞菌、金黄色葡萄球菌和粪肠球菌）和两种蠕虫肠道范例（丛毛单胞菌属，和枯草芽孢杆菌）。我们特别鉴定了新的假定感染应答基因，其上调是正常病原体抗性所需的（即，grl-21和ptr-18对E. faecalis），以及正常宿主应激处理所需的肠道特异性宿主基因表达变化。重要的是，相互作用似乎比共享更具有微生物特异性。因此，我们的研究结果牵连刺猬样信号通路的调制和可能微调线虫-微生物的相互作用，并支持的想法，针对这一途径的干预可能提供一个新的途径驱虫剂的发展。本研究中采用的方法的图形摘要。结合C.线虫-微生物转录组学（1）和基因组织表达图谱（2），以及宿主基因失活后的高通量应激和感染测定（3），可以指导预测并加速鉴定线虫-微生物相互作用中涉及的遗传相互作用。
Controlling nematode-caused diseases that affect cattle and crops world-wide remains a critical economic issue, owing to the lack of effective sustainable interventions. The interdependence of roundworms and their environmental microbes, including their microbiota, offers an opportunity for developing more targeted anthelminthic strategies. However, paucity of information and a currently narrow understanding of nematode-microbe interactions limited to specific infection contexts has precluded us from exploiting it. With the advent of omics approaches to map host-microbe genetic interactions, particularly in the model roundworm Caenorhabditis elegans, large datasets are now available across multiple models, that enable identification of nematode-microbe-specific pathways. In this work we collected 20 transcriptomic datasets documenting gene expression changes of C. elegans exposed to 20 different commensal and pathogenic microbes, performing gene enrichment analyses followed by functional testing using RNA interference directed toward genes of interest, before contrasting results from transcriptomic meta-analyses and phenomics. Differential expression analyses revealed a broad enrichment in signaling, innate immune response and (lipid) metabolism genes. Amongst signaling gene families, the nematode-divergent and expanded Hedgehog-like signaling (HHLS) pathway featured prominently. Indeed, 24/60 C. elegans Hedgehog-like proteins (HRPs) and 15/27 Patched-related receptors (PTRs) were differentially expressed in at least four microbial contexts, while up to 32/60 HRPs could be differentially expressed in a single context. interestingly, differentially expressed genes followed a microbe-specific pattern, suggestive of an adaptive microbe-specific response. To investigate this further, we knocked-down 96 individual HHLS genes by RNAi, using high-throughput assays to assess their impact on three worm-gut infection models (Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis) and two worm-commensal paradigms (Comamonas sp., and Bacillus subtilis). We notably identified new putative infection response genes whose upregulation was required for normal pathogen resistance (i.e., grl-21 and ptr-18 protective against E. faecalis), as well as commensal-specific host-gene expression changes that are required for normal host stress handling. Importantly, interactions appeared more microbe-specific than shared. Our results thus implicate the Hedgehog-like signaling pathway in the modulation and possibly fine-tuning of nematode-microbe interactions and support the idea that interventions targeting this pathway may provide a new avenue for anthelmintic development. Graphical abstract of the approach employed in this study. Combined analyses of C. elegans-microbe transcriptomics (1) and gene tissue expression maps (2), with high-throughput stress and infection assays following host-gene inactivation (3), can guide predictions and accelerate identification of genetic interactions involved in nematode-microbe interactions.
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DOI：
10.1073/pnas.1312087110
发表时间：
2013-10-01
影响因子：
11.1
作者：
Berkseth, Matt;Ikegami, Kohta;Zarkower, David
通讯作者：
Zarkower, David
影响因子：
4.5
作者：
Chiyoda H;Kume M;Del Castillo CC;Kontani K;Spang A;Katada T;Fukuyama M
通讯作者：
Fukuyama M
影响因子：
30.8
作者：
International Helminth Genomes Consortium
通讯作者：
International Helminth Genomes Consortium
影响因子：
4.5
作者：
Fernandes de Abreu DA;Caballero A;Fardel P;Stroustrup N;Chen Z;Lee K;Keyes WD;Nash ZM;López-Moyado IF;Vaggi F;Cornils A;Regenass M;Neagu A;Ostojic I;Liu C;Cho Y;Sifoglu D;Shen Y;Fontana W;Lu H;Csikasz-Nagy A;Murphy CT;Antebi A;Blanc E;Apfeld J;Zhang Y;Alcedo J;Ch'ng Q
通讯作者：
Ch'ng Q
影响因子：
10.5
作者：
HODGKIN, J
通讯作者：
HODGKIN, J