Molecular Genetics of Innate Immunity in C. elegans

描述(申请人提供)：对环境和内源微生物的进化适应塑造了多细胞生物体的免疫力和生理学。对哺乳动物和果蝇先天免疫的遗传研究趋同，揭示了古老的宿主防御信号通路的共性，促使我开始对简单寄主生物秀丽线虫的先天免疫进行分子遗传学分析。该项目的长期目标是了解线虫宿主防御的分子机制，期望对这种简单的宿主生物的研究将有助于揭示天然免疫的保守机制以及宿主与微生物相互作用的进化和生理。在上一次资助期间，我们继续建立线虫的先天免疫机制，同时也扩大了我们的工作，以涵盖宿主对感染反应的综合生理学。我们发现了未折叠蛋白反应在先天性免疫耐受中的生理作用，并定义了神经基因的多态性如何调节致病细菌的行为回避，强调了神经系统在对微生物的反应中的作用。我们还启动了一项研究，以了解线虫免疫衰老的分子基础，即与年龄相关的免疫功能下降。我们对线虫宿主的研究强调了微生物病原体和天然免疫激活对宿主生理的影响。在这一更新应用中，我们汇集了从这些研究中获得的一些见解，并将注意力转向宿主-微生物相互作用如何影响衰老和先天免疫的生理学。我们提出的基本假设是，微生物可以通过调节神经内分泌信号通路影响线虫宿主的寿命和免疫力。我们的初步研究已经确定了在宿主防御的神经内分泌调节中对转化生长因子-生长因子信号通路的要求。此外，我们观察到病原体诱导的宿主神经元基因表达的显著变化，这是我们用单分子荧光原位杂交方法定量定义的。我们有三个目标。首先，我们将定义转化生长因子-生长因子途径如何促进宿主对病原菌的防御，并评估该途径在免疫衰老过程中的作用。其次，我们将确定宿主对微生物环境变化的反应和诱导神经元转化生长因子-ss表达的变化所涉及的感觉机制。第三，我们将确定微生物分子(S)和相应的遗传决定因素，这些分子通过依赖转化生长因子-ss的神经内分泌信号的变化来调节宿主生理。我们预计，这些研究将阐明宿主的微生物环境如何调节生理的各个方面，包括有助于衰老和长寿的过程。

DESCRIPTION (provided by applicant): Evolutionary adaptation to environmental and endogenous microbes has shaped the immunity and physiology of multicellular organisms. Convergent genetic studies of innate immunity in mammals and in Drosophila revealed a commonality in the ancient signaling pathways of host defense, motivating me to embark on the molecular genetic analysis of innate immunity in the simple host organism Caenorhabditis elegans. The long-term goal of this project is to understand the molecular mechanisms of host defense in C. elegans, with the anticipation that studies in this simple host organism will shed light on conserved mechanisms of innate immunity and the evolution and physiology of host-microbe interactions. During the last funding period, we have continued to establish the mechanisms of innate immunity in C. elegans, while also extending our work to encompass the integrative physiology of host responses to infection. We discovered a physiological role for the Unfolded Protein Response in innate immune tolerance and defined how polymorphisms in neuronal genes can modulate the behavioral avoidance of pathogenic bacteria, underscoring the role of the nervous system in responses to microbes. We also initiated a study to understand the molecular basis of immunosenescence in C. elegans, the age-associated decline in immune function. Our studies of the C. elegans host have emphasized the influence that microbial pathogens and innate immune activation can have on host physiology. In this renewal application, we bring together a number of insights gained from these studies and turn our attention to how host-microbe interactions influence the physiology of aging and innate immunity. The basic underlying hypothesis of our proposal is that microbial pathogens can influence longevity and immunity of the C. elegans host through the modulation of neuroendocrine signaling pathways. Our preliminary studies have established a requirement for the TGF-ss signaling pathway in the neuroendocrine regulation of host defense. In addition, we observe marked pathogen-induced changes in host neuronal gene expression that we have defined quantitatively using single-molecule fluorescent in situ hybridization methods. We have three aims. First, we will define how the TGF-ss pathway promotes host defense against pathogenic bacteria and assess the role of this pathway during immunosenescence. Second, we will define the host sensory mechanisms involved in responding to changes in the microbial environment and inducing changes in neuronal TGF-ss expression. Third, we will identify the microbial molecule(s) and corresponding genetic determinants that modulate host physiology through changes in TGF-ss-dependent neuroendocrine signals. We anticipate that these studies will illuminate how the microbial environment of the host can modulate diverse aspects of physiology, including processes contributing to aging and longevity.