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: 10688199
• 负责人: Read Pukkila-Worley
• 金额: $ 59.04万
• 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/10688199
• 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; Homologous Gene; Host Defense; Immune; Immune signaling; Immune system; Immunity; Infection; Inflammatory; Intestines; Lead; Length; Lipids; MED15; Mammals; 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 Recognition; Pattern recognition receptor; Phenotype; Phospholipids; Physiology; Plants; Plasma Cells; Process; Resistance; Signal Transduction; commensal bacteria; commensal microbes; detection platform; enteric infection; fluidity; gene synthesis; 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.

项目摘要 对致病细菌的先天识别涉及感知物理存在的潜在有害 伴随感染的微生物和宿主生理的扰动。通过监视 宿主的病原体感染，而不是感染微生物本身，监测免疫 使宿主能够在感染期间将免疫防御措施指向善意的病原体 共生细菌。监视免疫的概念首先在植物和线虫中描述 秀丽隐杆线虫，随后，在哺乳动物中表征了一些特定的例子。但是，是 未知病原体诱导的宿主生理变化如何激活免疫防御。 在这里，我们推进了先天免疫感的新假设，该假设源于监视的概念 免疫。该提议的中心假设是病原体感染会导致流动性的变化 宿主感知的肠质膜是诱导先天免疫防御的。具体来说，我们 提出病原体感染改变了血浆磷脂室中的脂肪酸去饱和度 膜，可降低其流动性并导致细胞内免疫信号级联反应的激活。 通过线虫秀丽隐杆线虫中宿主 - 病原体相互作用的遗传研究，我们做了几个 为此思想提供基本原理的观察结果：（i）监测膜流动动力学以激活 先天免疫防御。脂肪酸生物发生和去饱和的转录调节剂的破坏 降低膜的流动性并以概括肠道感染的方式引起免疫激活 通过细菌病原体。 （ii）p38 pmk-1先天免疫途径是线虫的宿主防御途径，是 在具有膜流动性病理学的秀丽隐杆线虫突变体中激活。 （iii）病原体感染迅速耗尽 宿主脂肪酸并抑制合成单不饱和脂肪酸的基因的转录。 重要的是，我们发现病原体感染也破坏了肠上皮细胞血浆的流动性 膜。 （iv）最后，病原体耐药性需要细胞膜流动性。秀丽隐杆线虫突变体与 膜流动性缺陷是病原体感染的超敏感性，并恢复膜流动性 动力学补充了这种突变表型。 在此提案中，我们将表征肠细胞质膜流动性的宿主监测为一种新型 激活先天免疫力的机制（AIM 1）。我们还将定义病原体引起的变化 降低质膜流动性的膜组成（AIM 2）并确定p38的机理 细菌感染期间的PMK-1途径激活（AIM 3）。拟议的研究将定义一般策略 秀丽隐杆线虫用来检测病原体诱导的宿主生理障碍，揭示了基本 洞悉以前未被认可的，进化上古老的免疫激活策略。