Detection of pathogen infection by monitoring host cell membrane dynamics

项目总结 对致病细菌的先天识别包括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的扰动。通过监测 病原体对宿主的感染而不是对感染微生物本身的监控免疫 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，随后，一些特定的例子已经在哺乳动物中被描述出来。然而，它是 尚不清楚病原体诱导的宿主生理变化如何激活免疫防御。 在这里，我们提出了一种新的先天免疫感知假说，该假说源于监视的概念 豁免权。这一建议的中心假设是病原体感染导致细胞流动性的改变。 肠道质膜，被宿主感知以诱导天然免疫防御。具体来说，我们 认为病原体感染改变了血浆磷脂室的脂肪酸去饱和度 膜，这降低了它们的流动性，并导致激活细胞内的免疫信号级联。 通过对线虫寄主-病原体相互作用的遗传学研究，我们得到了几个 为这一想法提供理论基础的观察结果：(I)膜流动性动态被监测以激活 先天免疫防御系统。脂肪酸生物合成和去饱和度的转录调节因子的干扰 降低细胞膜流动性，导致免疫激活，从而重演肠道感染 被细菌病原体感染。(Ii)线虫的宿主防御途径p38PMK-1先天免疫途径是 在具有膜流动性病理的线虫突变体中被激活。(三)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转录。 重要的是，我们发现病原体感染也扰乱了肠上皮细胞浆的流动性。 膜。(4)最后，细胞膜流动性是抗病原菌所必需的。线虫突变体与 膜流动性缺陷对病原体感染过敏，膜流动性恢复 动力学补充了这种突变表型。 在这项提案中，我们将把宿主对肠道细胞质膜流动性的监测描述为一种新的 激活先天免疫机制(目标1)。我们还将定义病原体诱导的变化 降低质膜流动性的膜成分(目标2)和确定p38的机制 细菌感染时PMK-1通路的激活(目标3)。拟议的研究将确定一个总体战略 线虫用来检测病原体诱导的寄主生理紊乱，揭示了基本的 对一种以前未被认识的、进化上古老的免疫激活策略的洞察。

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.