Tscherner Michael, Giessen Tobias W, Markey Laura, Kumamoto Carol A, Silver Pamela A
Department of Systems Biology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
Wyss Institute for Biologically Inspired Engineering , Harvard University , Boston , Massachusetts 02115 , United States.
ACS Synth Biol. 2019 Feb 15;8(2):434-444. doi: 10.1021/acssynbio.8b00457. Epub 2019 Jan 16.
Due to a limited set of antifungals available and problems in early diagnosis, invasive fungal infections caused by Candida species are among the most common hospital-acquired infections with staggering mortality rates. Here, we describe an engineered system able to sense and respond to the fungal pathogen Candida albicans, the most common cause of candidemia. In doing so, we identified hydroxyphenylacetic acid (HPA) as a novel molecule secreted by C. albicans. Furthermore, we engineered E. coli to be able to sense HPA produced by C. albicans. Finally, we constructed a sense-and-respond system by coupling the C. albicans sensor to the production of an inhibitor of hypha formation, thereby reducing filamentation, virulence factor expression, and fungal-induced epithelial damage. This system could be used as a basis for the development of novel prophylactic approaches to prevent fungal infections.
由于可用的抗真菌药物种类有限以及早期诊断存在问题,念珠菌属引起的侵袭性真菌感染是最常见的医院获得性感染之一,死亡率惊人。在此,我们描述了一种能够感知并响应真菌病原体白色念珠菌(念珠菌血症最常见的病因)的工程系统。在此过程中,我们鉴定出对羟基苯乙酸(HPA)是白色念珠菌分泌的一种新分子。此外,我们对大肠杆菌进行工程改造,使其能够感知白色念珠菌产生的HPA。最后,我们通过将白色念珠菌传感器与菌丝形成抑制剂的产生相耦合,构建了一个感知与响应系统,从而减少菌丝形成、毒力因子表达以及真菌诱导的上皮损伤。该系统可作为开发预防真菌感染新方法的基础。