Detection of pathogen infection by monitoring host cell membrane dynamics

通过监测宿主细胞膜动力学检测病原体感染

• 批准号: 10685141
• 负责人: Read Pukkila-Worley
• 金额: $ 8.09万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685141
• 关键词: 20 year old; Bacterial Infections; Biogenesis; Caenorhabditis elegans; Cell membrane; Cells; Communicable Diseases; Complement; Complex; Data; Defect; Epithelial Cells; Fatty Acids; Genes; Genetic Transcription; Genetic study; Homeostasis; Host Defense; Immune; Immune signaling; Immune system; Immunity; Infection; Inflammatory; Intestines; Lead; Length; Lipids; MED15; Mammals; Marshal; Membrane; Membrane Fluidity; Membrane Lipids; Microbe; Molecular; Monitor; Monounsaturated Fatty Acids; Morbidity - disease rate; NAD+ Nucleosidase; Natural Immunity; Nematoda; Pathogen detection; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Phospholipids; Physiology; Plants; Plasma Cells; Process; Resistance; Signal Transduction; commensal bacteria; commensal microbes; enteric infection; fluidity; immune activation; innate immune pathways; innate immune sensing; insight; intestinal epithelium; microorganism; mortality; mutant; novel; p38 Mitogen Activated Protein Kinase; pathogen; pathogenic bacteria; pathogenic microbe; response; restoration; stem

PROJECT SUMMARY Innate recognition of pathogenic bacteria involves sensing both the physical presence of potentially harmful microbes and the perturbations of host physiology that accompany infection. By monitoring for the effects of pathogen infection on the host rather than for the infectious microorganism itself, surveillance immunity enables the host to direct immune defenses towards bona fide pathogens during an infection and not harmless commensal bacteria. The concept of surveillance immunity was first described in plants and in the nematode C. elegans, and subsequently, a few specific examples have been characterized in mammals. However, it is unknown how pathogen-induced changes in host physiology activate immune defenses. Here, we advance a new hypothesis of innate immune sensing that stems from the concept of surveillance immunity. The central hypothesis of this proposal is that pathogen infection causes a change in the fluidity of intestinal plasma membranes, which is sensed by the host to induce innate immune defenses. Specifically, we propose that pathogen infection alters fatty acid desaturation in the phospholipid compartment of plasma membranes, which reduces their fluidity and leads to activation of intracellular immune signaling cascades. Through genetic studies of host-pathogen interactions in the nematode C. elegans, we made several observations that provide the rationale for this idea: (i) Membrane fluidity dynamics are monitored to activate innate immune defenses. Disruption of a transcriptional regulator of fatty acid biogenesis and desaturation decreases membrane fluidity and causes immune activation in a manner that recapitulates intestinal infection by bacterial pathogens. (ii) The p38 PMK-1 innate immune pathway, a host defense pathway of nematodes, is activated in C. elegans mutants that have membrane fluidity pathology. (iii) Pathogen infection rapidly depletes host fatty acids and suppresses the transcription of genes that synthesize monounsaturated fatty acids. Importantly, we found that pathogen infection also disrupts the fluidity of intestinal epithelial cell plasma membranes. (iv) Finally, cell membrane fluidity is required for pathogen resistance. C. elegans mutants with defects in membrane fluidity are hypersusceptible to pathogen infection, and restoration of membrane fluidity dynamics complements this mutant phenotype. In this proposal, we will characterize host surveillance of intestinal cell plasma membrane fluidity as a novel mechanism to activate innate immunity (Aim 1). We will also define the pathogen-induced changes in membrane composition that decrease plasma membrane fluidity (Aim 2) and determine the mechanism of p38 PMK-1 pathway activation during bacterial infection (Aim 3). The proposed study will define a general strategy employed by C. elegans to detect pathogen-induced disturbances in host physiology, revealing fundamental insights into a previously unrecognized, evolutionarily ancient strategy of immune activation.

项目概要 对病原菌的先天识别涉及感知潜在有害物质的物理存在 微生物和伴随感染的宿主生理学的扰动。通过监测影响 病原体感染宿主而不是感染微生物本身，监视免疫 使宿主能够在感染期间针对真正的病原体进行免疫防御，而不是无害的 共生细菌。监视免疫的概念首先在植物和线虫中被描述 线虫以及随后的一些具体例子在哺乳动物中得到了表征。然而，它是 目前尚不清楚病原体引起的宿主生理变化如何激活免疫防御。 在这里，我们提出了一种源于监视概念的先天免疫传感的新假设 免疫。该提案的中心假设是病原体感染导致流动性的变化 肠道质膜，被宿主感知以诱导先天免疫防御。具体来说，我们 提出病原体感染改变血浆磷脂区室中的脂肪酸去饱和度 膜，这降低了其流动性并导致细胞内免疫信号级联的激活。 通过对线虫秀丽隐杆线虫宿主-病原体相互作用的遗传学研究，我们制作了几种 为这一想法提供理论依据的观察结果：（i）监测膜流动性动力学以激活 先天免疫防御。脂肪酸生物发生和去饱和的转录调节因子的破坏 降低膜流动性并以重现肠道感染的方式引起免疫激活 由细菌病原体引起。 (ii) p38 PMK-1 先天免疫途径，线虫的宿主防御途径，是 在具有膜流动性病理学的线虫突变体中被激活。 (iii) 病原体感染迅速减少 宿主脂肪酸并抑制合成单不饱和脂肪酸的基因转录。 重要的是，我们发现病原体感染也会破坏肠上皮细胞血浆的流动性 膜。 (iv) 最后，细胞膜流动性是病原体抵抗力所必需的。线虫突变体 膜流动性缺陷对病原体感染非常敏感，膜流动性的恢复 动力学补充了这种突变表型。 在本提案中，我们将把宿主对肠细胞质膜流动性的监测描述为一种新颖的方法。 激活先天免疫的机制（目标 1）。我们还将定义病原体引起的变化 降低质膜流动性的膜成分（目标 2）并确定 p38 的机制 细菌感染期间 PMK-1 通路激活（目标 3）。拟议的研究将确定总体策略 秀丽隐杆线虫用来检测病原体引起的宿主生理紊乱，揭示了基本原理 深入了解以前未被认识的、进化上古老的免疫激活策略。