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，尽管越来越多的人认识到微生物组细菌影响的无数方式， 然而，在人类健康方面，细菌用来影响宿主的大多数信号仍然未知。这项建议旨在 利用我们团队独特的专业知识和最近的发现， 可以直接感知和响应细菌的小RNA（sRNA）。 自从20世纪20年代发现抗生素以来，致病机理领域主要集中在小的 分子：几乎所有已知的抗生素和细菌信号分子都是小分子。但我们非常 需要新的正交方法。基于核酸的疗法已经成为一个令人兴奋的新平台， 药物快速发展。由于它们的化学相似性，建立了核酸的药理学， 这样，一旦我们知道靶向什么序列，药物开发管道就相对简化了（在 至少与小分子药物相比）。例如，一名巴滕病患者最近成功地 在她的基因组测序后不到一年，她接受了个性化的合成反义RNA治疗。 基于RNA的干预通常不被考虑用于细菌，因为细菌RNA是 被认为只在细菌中发挥作用。然而，我们最近推翻了这一范式， 模型动物宿主可以直接“读取”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）机制来响应细菌sRNA。这一结果 特别令人兴奋的是，它表明了RNAi机制在感知中的一个先前未被认识的作用。 对细菌有反应。它还表明，了解基于sRNA的微生物宿主信号可能有助于 开发新的疗法，帮助宿主抵御病原体或促进细菌定植。然而，在这方面， 目前，由于我们缺乏关于抗微生物药物的知识， 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，我们建议建立在我们发现的sRNA宿主信号，以显着关闭这一知识 间隙这将在跨越多个宿主和微生物的三个互补部分中完成： 绘制人类肠道微生物群落sRNA-host相互作用和功能， 哺乳动物细胞对病原体sRNA有应答，使用C. elegans来表征 sRNA-host相互作用的机制。为了实现这些目标，我们将联合收割机结合我们团队的专业知识， 由人类微生物组和计算生物学（Donia）领域的领导者组成，微生物 致病机理和抗生素开发（Gitai），和C. elegans behavior and genomics（Murphy）.我们 因此，联合努力有可能为微生物-宿主相互作用建立新的范例，并为微生物-宿主相互作用铺平道路。 找到急需的新疗法

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.