Small RNAs as Novel Modulators of Microbe-Host Interactions

抗生素耐药性的增加严重耗尽了我们对抗致命细菌的武器库 病原体。与此同时，尽管人们越来越多地认识到微生物群细菌影响的各种方式 在人类健康方面，细菌用来影响宿主的大多数信号仍不清楚。这项建议旨在 通过利用我们团队的独特专业知识和最近发现的动物 可以直接感知和响应细菌的小RNA(SRNA)。 自从20世纪20年代抗生素被发现以来，发病机制领域主要集中在小分子。 分子：几乎所有已知的抗生素和细菌信号分子都是小分子。但我们痛心地 需要新的、正交化的方法。基于核酸的疗法已经成为一个令人兴奋的新平台 快速的药物开发。由于它们的化学相似性，核酸的药理学被建立起来， 这样，一旦我们知道目标序列，药物开发流水线就相对简化了(在 与小分子药物相比最低)。例如，一名巴顿病患者最近成功地 在她的基因组测序不到一年后，用个性化的合成反义RNA进行了治疗。 基于RNA的干预通常不被考虑用于细菌，因为细菌的RNA是 被认为只在细菌内起作用。然而，我们最近推翻了这个范例，证明了 该模型动物宿主可以直接读取由人类病原体假单胞菌产生的sRNA 铜绿假单胞菌，使用RNA干扰(RNAi)机制对细菌sRNA做出反应。这个结果是 特别令人兴奋的是，它暗示了RNAi机制在传感方面以前没有得到重视的作用 以及对细菌的反应。它还表明，理解基于sRNA的微生物-宿主信号可能会有所帮助 开发新的疗法来帮助宿主抵御病原体或促进共生殖民。然而， 推进这种新的抗菌战略目前受到我们缺乏关于 SRNA介导的细菌-宿主相互作用的空间及其发挥作用的分子机制。 在这里，我们建议以我们对sRNA-host信号的发现为基础，显著地结束这一知识 差距。这将通过跨越多个宿主和微生物的三个互补部分来完成：全球 绘制人类肠道微生物群落sRNA-宿主相互作用和功能图，确定如何 哺乳动物细胞对病原体sRNA做出反应，并使用线虫来表征分子 SRNA-宿主相互作用的机制。为了实现这些目标，我们将结合我们团队的专业知识， 由人类微生物群和计算生物学(DONIA)、微生物 致病机制和抗生素开发(Gitai)，以及线虫行为和基因组学(Murphy)。我们的 因此，联合努力有可能建立微生物-宿主相互作用的新范式，并为 通往急需的新疗法之路。

The rise in antibiotic resistance has severely depleted our arsenal for combatting deadly bacterial pathogens. Meanwhile, despite increased appreciation of the myriad ways that microbiome bacteria impact human health, most of the signals that bacteria use to influence hosts remain unknown. This proposal seeks to address both of these challenges by leveraging our team’s unique expertise and recent discovery that animals can directly sense and respond to bacterial small RNAs (sRNAs). Since the discovery of antibiotics in the 1920s, the pathogenesis field has primarily focused on small molecules: nearly all known antibiotics and bacterial signaling molecules are small molecules. But we sorely need new, orthogonal approaches. Nucleic acid-based therapies have emerged as an exciting new platform for rapid drug development. Due to their chemical similarity, the pharmacology of nucleic acids is established, such that once we know what sequence to target, the drug development pipeline is relatively streamlined (at least in comparison to small molecule drugs). For example, a Batten disease patient was recently successfully treated with a personalized synthetic antisense RNA, less than a year after her genome was sequenced. RNA-based interventions have typically not been considered for bacteria because bacterial RNAs were thought to function exclusively within the bacteria. However, we recently overturned this paradigm by proving that model animal hosts can directly “read” the sRNAs produced by the human pathogen, Pseudomonas aeruginosa, using the RNA-interference (RNAi) machinery to respond to the bacterial sRNAs. This result is particularly exciting because it suggests a previously unappreciated role for the RNAi machinery in sensing and responding to bacteria. It also suggests that understanding sRNA-based microbe-host signaling could help develop new therapies to help hosts ward off pathogens or promote commensal colonization. However, advancing such new antimicrobial strategies is currently hindered by our lack of knowledge regarding the space of sRNA-mediated bacteria-host interactions and the molecular mechanisms by which they function. Here, we propose to build off our discovery of sRNA-host signaling to significantly close this knowledge gap. This will be accomplished in three complementary parts that span multiple hosts and microbes: globally mapping human gut microbiome community sRNA-host interactions and functions, determining how mammalian cells respond to pathogen sRNAs, and using C. elegans to characterize the molecular mechanisms of sRNA-host interactions. To achieve these goals we will combine the expertise of our team, comprised of leaders in the fields of human microbiome and computational biology (Donia), microbial pathogenesis and antibiotic development (Gitai), and C. elegans behavior and genomics (Murphy). Our combined efforts thus have the potential to establish new paradigms for microbe-host interactions and pave the way to desperately-needed new therapies.