State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Host Microbe. 2024 Feb 14;32(2):276-289.e7. doi: 10.1016/j.chom.2023.12.012. Epub 2024 Jan 11.
Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis. By exploring stationary-phase indicator molecules and developing single-cell tracking strategies, we show that in the lung, AmB persisters are enriched in cryptococcal cells that abundantly produce stationary-phase molecules. The antioxidant ergothioneine plays a specific and key role in AmB persistence, which is conserved in phylogenetically distant fungi. Furthermore, the antidepressant sertraline (SRT) shows potent activity specifically against cryptococcal AmB persisters. Our results provide evidence for and the determinant of AmB-tolerant persister formation in pulmonary cryptococcosis, which has potential clinical significance.
细菌持久体是一种亚群细胞，具有遗传易感性，通常处于休眠状态且对杀菌剂具有耐受性，因其具有临床重要性而受到广泛研究。相比之下，对于真菌持久体形成的决定因素知之甚少。在这里，我们报告在小鼠肺部感染期间，新生隐球菌形成了对两性霉素 B（AmB）高度耐受的持久体，AmB 是治疗隐球菌病的标准治疗方法。通过探索静止期指示分子并开发单细胞跟踪策略，我们表明在肺部，AmB 持久体在大量产生静止期分子的隐球菌细胞中富集。抗氧化剂麦角硫因在 AmB 持续存在中发挥特异性和关键作用，这在系统发育上差异很大的真菌中是保守的。此外，抗抑郁药舍曲林（SRT）对隐球菌 AmB 持久体具有特异的活性。我们的研究结果为肺部隐球菌病中 AmB 耐受持久体的形成提供了证据和决定因素，这具有潜在的临床意义。
