Candida albicans is an opportunistic pathogen that colonizes diverse mucosal niches with distinct environmental characteristics. To adapt to these different sites, C. albicans must activate and attenuate a variety of signal transduction pathways. A mechanism of signal attenuation is through receptor endocytosis and subsequent vacuolar degradation, which requires the endosomal sorting complex required for transport (ESCRT) pathway. This pathway comprises several polyprotein complexes (ESCRT-0, -I, -II, -III, and -DS) that are sequentially recruited to the endosomal membrane. The ESCRT pathway also activates the Rim101 transcription factor, which governs expression of genes required for virulence. Here, we tested the hypothesis that the ESCRT pathway plays a Rim101-independent role(s) in pathogenesis. We generated deletion mutants in each ESCRT complex and determined that ESCRT-I, -II, and -III are required for Rim101 activation but that ESCRT-0 and ESCRT-DS are not. We found that the ESCRT-0 member Vps27 and ESCRT-DS components are required to promote epithelial cell damage and, using a murine model of oral candidiasis, found that the vps27Delta/Delta mutant had a decreased fungal burden compared to that of the wild type. We found that a high-dose inoculum can compensate for fungal burden defects but that mice colonized with the vps27Delta/Delta strain exhibit less morbidity than do mice infected with the wild-type strain. These results demonstrate that the ESCRT pathway has Rim101-independent functions for C. albicans virulence.

译文

:白色念珠菌是一种机会病原体,它定居在具有独特环境特征的各种粘膜壁ni中。为了适应这些不同的位置,白色念珠菌必须激活并减弱各种信号转导途径。信号衰减的机制是通过受体内吞作用和随后的液泡降解,这需要转运所需的内体分选复合物(ESCRT)途径。该途径包含依次募集到内体膜的几种多蛋白复合物(ESCRT-0,-I,-II,-III和-DS)。 ESCRT途径还激活Rim101转录因子,该因子控制毒力所需基因的表达。在这里,我们测试了ESCRT途径在发病机制中起Rim101独立作用的假设。我们在每个ESCRT复合物中生成了缺失突变体,并确定ESCRT-1,-II和-III是激活Rim101所必需的,而ESCRT-0和ESCRT-DS不是必需的。我们发现ESCRT-0成员Vps27和ESCRT-DS成分是促进上皮细胞损伤所必需的,并且使用口腔念珠菌病的鼠模型,发现vps27Delta / Delta突变体与野生型相比具有降低的真菌负担。我们发现高剂量接种物可以补偿真菌负荷缺陷,但是定居于vps27Delta / Delta菌株的小鼠的发病率要低于感染野生型菌株的小鼠。这些结果表明,ESCRT途径对白色念珠菌的毒力具有Rim101独立的功能。

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