Santos Rui, Costa Catarina, Mil-Homens Dalila, Romão Daniela, de Carvalho Carla C C R, Pais Pedro, Mira Nuno P, Fialho Arsénio M, Teixeira Miguel C
Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
Biological Sciences Research Group, IBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Lisbon, Portugal.
Cell Microbiol. 2017 May;19(5). doi: 10.1111/cmi.12686. Epub 2017 Jan 3.
The mechanisms of persistence and virulence associated with Candida glabrata infections are poorly understood, limiting the ability to fight this fungal pathogen. In this study, the multidrug resistance transporters CgTpo1_1 and CgTpo1_2 are shown to play a role in C. glabrata virulence. The survival of the infection model Galleria mellonella, infected with C. glabrata, was found to increase upon the deletion of either CgTPO1_1 or CgTPO1_2. The underlying mechanisms were further explored. In the case of CgTpo1_1, this phenotype was found to be consistent with the observation that it confers resistance to antimicrobial peptides (AMP), such as the human AMP histatin-5. The deletion of CgTPO1_2, on the other hand, was found to limit the survival of C. glabrata cells when exposed to phagocytosis and impair biofilm formation. Interestingly, CgTPO1_2 expression was found to be up-regulated during biofilm formation, but and its deletion leads to a decreased expression of adhesin-encoding genes during biofilm formation, which is consistent with a role in biofilm formation. CgTPO1_2 expression was further seen to decrease plasma membrane potential and affect ergosterol and fatty acid content. Altogether, CgTpo1_1 and CgTpo1_2 appear to play an important role in the virulence of C. glabrata infections, being at the cross-road between multidrug resistance and pathogenesis.
与光滑念珠菌感染相关的持续存在和毒力机制尚不清楚，这限制了对抗这种真菌病原体的能力。在本研究中，多药耐药转运蛋白CgTpo1_1和CgTpo1_2被证明在光滑念珠菌的毒力中起作用。在用光滑念珠菌感染的大蜡螟感染模型中，发现缺失CgTPO1_1或CgTPO1_2后，感染模型的存活率会增加。对其潜在机制进行了进一步探索。就CgTpo1_1而言，发现该表型与它赋予对抗菌肽（如人抗菌肽组蛋白-5）的抗性这一观察结果一致。另一方面，发现缺失CgTPO1_2会限制光滑念珠菌细胞在吞噬作用下的存活，并损害生物膜形成。有趣的是，发现CgTPO1_2在生物膜形成过程中表达上调，但其缺失会导致生物膜形成过程中黏附素编码基因的表达降低，这与它在生物膜形成中的作用一致。进一步发现CgTPO1_2表达会降低质膜电位并影响麦角固醇和脂肪酸含量。总之，CgTpo1_1和CgTpo1_2似乎在光滑念珠菌感染的毒力中起重要作用，处于多药耐药和发病机制的交叉点。
