Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.

肠道病原体是一组主要的致病物质，必须克服身体和 胃肠道的免疫屏障。驻留的微生物群呈现出大量的配体 和病原体相关分子模式(PAMP)，通过模式启动免疫防御 肠细胞和免疫常驻细胞上的识别受体(PRRs)。事实上，微生物衍生的TLR 配体是发展和维持肠道屏障和免疫稳态所必需的。 此外，微生物区系不是静态的和不平衡的细菌群落，称为生态失调、影响免疫、 尤其是在老化过程中。衰老与肠道病原体的易感性增加有关，以及 益生菌群改变敏感性在很大程度上是未知的。微生物衍生配体的补充物 可以启动抗病毒免疫是不完整的。更好地理解分子 维持免疫的机制，微生物区系和上皮细胞如何相互作用，以及这是如何影响的 感染和发病机制有可能揭示治疗肠道病毒感染的新策略。研究 探索肠道感染中微生物区系和宿主基因在衰老背景下的作用是具有挑战性的 在小动物模型中，由于成本和技术障碍。为了克服我们对分子的认识上的差距 控制肠道病毒感染的机制，我们开发了一个口服感染模型，使用强大的 遗传模式生物果蝇。我们发现肠道对感染有很高的屏障：年轻的野生型 苍蝇对人类病毒的口服攻击是难以抵抗的，而接种到体腔中则绕过了 肠道，导致强烈的感染。肠道中参与的抗病毒途径的光谱，以及微生物区系如何 肠道中的形状免疫机制尚不完全清楚。初步发现，果蝇叮咬 控制肠道感染；dSTING突变更容易受到肠道病毒感染。斯汀是众所周知的 被环二核苷酸(CDN)激活。虽然cGAS可以内源性地产生CDN，但刺痛也可以 被细菌衍生的CDN激活。这让我们探索了一种可能性，即共生细菌起源于 CDN可能通过刺痛影响肠道的先天防御，因为众所周知，微生物来源的CDN是 存在于肠道中。我们的新数据确定了微生物来源的CDN在抗病毒防御中的作用。烧蚀 幼年动物体内的微生物群会导致感染增加，而喂食这些微生物区系缺陷的果蝇CDN 是保护性的。在目标1中，我们将定义dSTING在抗病毒防御中的作用，在目标2中，我们将定义该角色 幼年和老年动物的共生CDN在抗病毒防御中的应用。

Enteric pathogens represent a major group of disease-causing agents, and must overcome the physical and immunological barrier of the gastrointestinal tract. The resident microbiota presents with a large array of ligands and pathogen-associated molecular patterns (PAMPs) which can prime immune defenses, through pattern recognition receptors (PRRs), both on enterocytes and immune resident cells. Indeed, microbial-derived TLR ligands are necessary for the development and maintenance of the intestinal barrier and immune homeostasis. Moreover, the microbiota is not static and imbalanced bacterial communities, termed dysbiosis, impact immunity, in particular during aging. Aging is associated with increased susceptibility to enteric pathogens, and how the dysbiotic microbiota alters susceptibility is largely unknown. The complement of microbial-derived ligands that are sensed and that can prime antiviral immunity is incomplete. A better understanding of the molecular mechanisms by which immunity is maintained, how the microbiota and epithelia interact, and how this impacts infection and pathogenesis has the potential to reveal novel strategies to treat enteric viral infections. Studies exploring the role of the microbiota and host genes in the context of aging in enteric infections are challenging in small animal models due to costs and technical hurdles. To overcome our gap in knowledge of the molecular mechanisms that control enteric viral infection, we developed an oral model of infection using the powerful genetic model organism, Drosophila. We found that the gut presents a high barrier to infection: young wild type flies are refractory to oral challenge with human viruses, while inoculation into the body cavity, which bypasses the gut, results in robust infection. The spectrum of antiviral pathways engaged in the gut, and how the microbiota shapes immunity in the intestine is incompletely understood. Preliminarily, we found that Drosophila STING controls infection in the intestine; dSTING mutants are more susceptible to enteric viral infection. STING is known to be activated by cyclic dinucleotides (CDNs). While cGAS can produce CDNs endogenously, STING can also be activated by bacterially derived CDNs. This led us to explore the possibility that commensal bacteria-derived CDNs may impact innate defenses in the gut through STING, as it is known that microbiota-derived CDNs are present in the gut. Our new data identifies a role for microbiota-derived CDNs in antiviral defense. Ablation of the microbiota in young animals leads to increased infection, and feeding these microbiota-deficient flies CDNs was protective. In Aim 1 we will define the role of dSTING in antiviral defense and in Aim 2 we will define the role of commensal-derived CDNs in antiviral defense in young and old animals.