Antiviral immunity in the gut: how the intestinal epithelium and microbiota regulate infection

 描述（由申请人提供）肠道病原体代表了一组主要的致病因子，必须克服肠道环境中的屏障免疫才能感染宿主。为了解决这个问题，胃肠道已经发展成为一个物理和免疫屏障。此外，许多肠道病毒感染肠上皮细胞，肠上皮细胞既是感染的靶标，又充当感染的哨兵。越来越多的证据表明，上皮细胞直接感知感染以诱导抗菌途径。同样清楚的是，肠道内的微生物群在免疫中起着重要作用，不平衡的细菌群落对免疫防御具有有害的后果。衰老的动物表现出免疫缺陷和微生物组的改变。从机制上讲，哪些微生物或微生物配体介导这些作用以及它们如何影响抗病毒免疫尚不清楚。为了克服我们在控制肠道病毒感染的分子机制方面的知识差距，我们使用强大的遗传模式生物果蝇（Drosophila melanogaster）开发了一种虫媒病毒感染的口服模型。我们发现，肠道对感染具有很高的屏障：年轻的野生型果蝇对肠道病毒的口服攻击很难抵抗，而接种到绕过肠道的体腔中会导致强烈的感染。重要的是，我们发现ERK通路在肠上皮中被感染激活，并且仅在肠上皮中ERK通路的遗传缺失导致感染增加。此外，我们发现微生物群在感染易感性中起着重要作用。在年轻的果蝇中，肠道中的唾液酸损失导致对病毒感染的抵抗力增加，这表明来自微生物群的信号影响先天信号。然而，我们发现存在生态失调的老年果蝇更容易受到口腔病毒感染。在这些条件下，切除盲肠可保护动物免受肠道病毒感染。因此，根据其组成，微生物群可以是保护性的，也可以是有害的。在这项提案中，我们将通过确定微生物群和上皮细胞控制肠道对人类病毒的免疫力的机制来解决抗病毒免疫中的基本问题，使用具有高度可操纵微生物组和短寿命的遗传易处理生物体。

 DESCRIPTION (provided by applicant) Enteric pathogens, which represent a major group of disease-causing agents, must overcome barrier immunity within the intestinal environment to infect a host. To counter this, the gastrointestinal tract has evolved as a physical and immunological barrier. Moreover, many enteric viruses infect intestinal epithelial cells which are both targets of and act as sentinels for infection. Increasing evidence suggests that epithelial cells sense infection directly to induce antimicrobial pathways. It is also clear that the microfloa within the intestinal tract plays a fundamental role in immunity and that imbalanced bacterial communities have detrimental consequences to immune defense. Aging animals present with immune deficiencies and an altered microbiome. Mechanistically, which microbes or microbial ligands, mediate these effects and how they impact antiviral immunity is unclear. To overcome our gap in knowledge of the molecular mechanisms that control enteric viral infection, we developed an oral model of arboviral infection using the powerful genetic model organism, Drosophila melanogaster. We found that the gut presents a high barrier to infection: young wild type flies are refractory to oral challenge with enteric viruses, while inoculation into the body cavity, which bypasses the gut, results in robust infection. Importantly, we found that the ERK pathway is activated in the intestinal epithelium by infection, and that genetic depletion of the ERK pathway only in the intestinal epithelium leads to increased infection. Furthermore, we found that the microbiota plays an important role in susceptibility to infection. In young flies, te loss of commensals in the gut led to increased permissivity to viral infection, suggesting that signals from the microbiota impact innate signaling. However, we found that older flies that present with dysbiosis are more susceptible to oral viral infection. Under these conditions ablation of the commensals protects the animals from enteric viral infection. Therefore, the microbiota, depending on its composition, can either be protective or detrimental for antiviral defenses. In this proposal we will address fundamental questions in antiviral immunity by determining the mechanisms by which the microbiota and epithelial cells control immunity in the intestine against human viruses, using a genetically tractable organism with a highly manipulable microbiome and short lifespan.