基于单细胞转录组技术研究细菌在药物刺激下的群体分化与命运决定

表型水平的适应性耐药是影响细菌整体耐药性的重要因素，而单细胞水平的异质性是其中的关键特征。尽管诸多研究表明药物刺激会导致细菌在基因表达和代谢等层面出现单细胞水平的异质性响应，并引起群体分化和最终的不同细胞命运，但研究手段的缺乏限制了在单细胞水平对此进行系统性刻画，以从分子层面深入理解这一关键进程。为此，本研究计划发展新一代更强大的细菌单细胞转录组技术，并以此为方法突破口，系统刻画细菌在药物刺激下的群体分化和最终命运决定，从而理解影响该过程动态演化和最终细胞命运分布的内在驱动因素，填补目前对这一影响细菌耐药的重要过程认识上的空白，以启发相关的临床诊疗。

As the first line of defense upon antibiotics treatment, adaptive tolerance at phenotypic level underlies bacterial survival, where heterogeneity at single cell level plays a key role. Many previous works suggested that antibiotics treatment gives rise to heterogenous response from gene expression to metabolism at single bacterial cell level; and further results in population differentiation and ultimately divergent fates in subpopulations. However, the limitation in currently available profiling methods hinders us from systematically shedding light on the dynamic landscapes and underlying driving factors of this functionally important process. To address this, we propose to develop a novel method, namely, single bacterial cell RNA-seq as a major technical innovation. Using this tool, we propose to systematically depict the population differentiation and cell fate of subpopulations upon drug stimuli, filling the major gap in profiling this important but less explored process that determines bacterial tolerance to antibiotics. In this line, we aim to decipher the underlying mechanism that drives the evolution of this dynamic process; and possibly inspire the development of novel therapy to fight bacterial infection.