Microevolution of pathogenic yeasts during interactions with the host immune system

白色念珠菌和念珠菌。光滑念珠菌是念珠菌血症的两个最重要的原因，念珠菌血症是一种危及生命的全身性真菌感染。作为寄生菌和机会致病菌，这些酵母菌必须能够适应人类宿主体内的许多不同生态位。我们的目标是使用在体外和体内强制微进化实验，以确定这些真菌适应宿主诱导的压力的能力，并确定新的潜在致病因子。为此，我们将首先暴露C。光滑的巨噬细胞在一系列的通道设置，并遵循遗传，表型，和转录的变化所诱导的恒定的宿主-真菌的相互作用。在第二种方法中，我们将使用C的突变体。白色念珠菌，其不能形成菌丝，这是毒力和逃避吞噬细胞所必需的性质。再次，突变体将在连续传代中暴露于巨噬细胞，并且将跟踪其存活和通过转录重布线重新获得菌丝形成的能力。最后，我们将研究C。白念珠菌适应不同的宿主生态位。在小鼠感染模型中，我们将遵循遗传和转录（转录重布线）的变化，以及连续重新分离和感染后真菌的嗜器官性的变化，我们将比较这与从不同宿主生态位获得的临床分离株的集合的数据。我们希望在这两种真菌中找到适应和机制，这可能构成新的“隐藏”致病因子。

Candida albicans and C. glabrata are the two most important causes of candidemia – a life-threatening, systemic fungal infection. As commensals and opportunistic pathogens, these yeasts have to be able to adapt to the many different niches inside their human host. We aim to use in vitro and in vivo forced microevolution experiments, both to determine the ability of these fungi to adapt to host-induced stresses, and to identify novel potential pathogenicity factors. To this end, we will first expose C. glabrata to macrophages in a serial passage setup and follow the genetic, phenotypic, and transcriptional changes induced by constant host-fungus interaction. In a second approach, we will use a mutant of C. albicans, which is unable to form hyphae, a property which is essential for virulence and escape from phagocytes. Again, the mutant will be exposed to macrophages in serial passages and its ability to survive and regain hyphal formation by transcriptional rewiring will be followed. Finally, we will investigate the ability of C. albicans to adapt to different host niches. In a murine infection model, we will follow the genetic and transcriptional (transcriptional rewiring) changes as well as changes of organotropism of the fungus after serial re-isolation and infection, and we will compare this to data from a collection of clinical isolates obtained from different host niches. We expect to find adaptations and mechanisms in both fungi, which may constitute novel, 'hidden' pathogenicity factors.