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Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis

针对菌丝对侧向酵母生长的调节机制作为对抗念珠菌病的新治疗方法

基本信息

批准号：
10447678
负责人：
PRIYA UPPULURI
金额：
$ 35.31万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2024-07-31
项目状态：
已结题

项目摘要

Abstract A single species Candida albicans, causes half of all invasive fungal infections in humans. The ability of C. albicans to switch reversibly between yeast and hyphe is a major virulence trait that helps it disseminate into the bloodstream (yeast) and invade target organs (filaments). Yeast to hyphae morphogenesis has been extensively studied and its regulation well understood. To the contrary, little is known about the reverse process: hyphae to yeast growth. C. albicans hyphae produce yeast cells from their lateral septal regions, coined as “lateral yeasts”. These lateral yeasts are always found with hyphae at the site of active infection, are the major cells that re- enter the bloodstream and establish distal foci of infection. In fact, lateral yeast cells released from the hyphal layers of biofilm-contaminated catheters have direct access into the bloodstream. We identified the first regulator of hyphae-to-lateral yeast growth, PES1 and have shown that blocking the process (by depleting PES1 in vivo) can abrogate disseminated candidiasis as well as biofilm- associated candidemia. Nothing is known on the regulatory aspects pf PES1. Our preliminary studies show that phosphorylation of Pes1 by Ras-PKA inhibits lateral yeast growth while its dephosphorylation by a Ras- linked phosphatase Yvh1 activates lateral yeast emergence from hyphae and induces biofilm dispersal. Using PES1 as a target for identifying small molecule inhibitors of lateral yeast growth, identified alexidine dihydrochloride that directly inhibited both Pes1 and Yvh1 and protected mice from biofilm-associated disseminated candidiasis. Here, using protein biochemistry assays, we propose to delineate how signaling through Ras-PKA regulates Pes1. We will identify other cognate regulators that interact with Pes1 to control lateral yeast growth, and use this information to discover novel compounds that can interrupt hyphae to lateral yeast growth and disseminated candidiasis. Ultimately, better outcomes for patients with indwelling medical devices is the goal of this application.

摘要一种单一的白色念珠菌，导致人类所有侵袭性真菌感染的一半。C. 白色念珠菌在酵母菌和菌丝之间可逆地转换是一个主要的毒力特征，有助于它传播到血液（酵母菌）和侵入目标器官（细丝）。酵母菌对菌丝形态发生的影响被广泛研究，并对其规则有很好的理解。相反，人们对相反的情况知之甚少过程：菌丝向酵母生长。C.白色念珠菌菌丝从它们的侧隔区产生酵母细胞，被称为“侧向酵母”这些侧生酵母菌总是在活动感染部位发现菌丝，是重新进入血流并建立远端感染灶的主要细胞。事实上，侧酵母从被生物膜污染的导管的菌丝层释放的细胞直接进入血流我们确定了菌丝到侧面酵母生长的第一个调节因子PES 1，并表明，阻断该过程（通过体内消耗PES 1）可以消除播散性念珠菌病以及生物膜- 相关念珠菌血症关于PES 1的监管方面尚不清楚。我们的初步研究显示 Pes 1被Ras-PKA磷酸化抑制酵母的侧向生长，而Pes 1被Ras-PKA去磷酸化抑制酵母的侧向生长。连接的磷酸酶Yvh 1激活酵母从菌丝中的侧向出现并诱导生物膜的分散。使用 PES 1作为鉴定酵母侧向生长的小分子抑制剂的靶标，鉴定了阿来西定二盐酸盐直接抑制Pes 1和Yvh 1，并保护小鼠免受生物膜相关的播散性念珠菌病在这里，使用蛋白质生物化学测定，我们建议描绘如何信号通过Ras-PKA调节Pes 1。我们将确定与Pes 1相互作用的其他同源调节因子，酵母侧向生长，并利用这些信息发现可以中断菌丝侧向生长的新型化合物酵母菌生长和播散性念珠菌病。最终，留置医疗器械的患者设备是本应用程序的目标。