Microbiology Division, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas, United States of America.
Office of Regulatory and Risk Management, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas, United States of America.
PLoS One. 2020 Oct 22;15(10):e0240789. doi: 10.1371/journal.pone.0240789. eCollection 2020.
In a recent study, using an in vitro model to study intravaginal nanoparticle exposure during yeast infections, we demonstrated that C. albicans exposure suppressed apoptotic gene expression and induced oxidative stress and pyroptosis in vaginal epithelial cells. The mucous-penetrating drug delivery nanoparticles made from poly-(D, L-lactic-co-glycolic acid)-(polyethylene glycol) induced cytotoxicity by activating apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and DNA damage repair responses alone and, in some cases with C. albicans. In the current study we evaluated the effects of fluorescently-labelled nanoparticles in CBA/J mice challenged intravaginally for two hours followed by intravaginal challenge with C. albicans for 18 hours. Nanoparticle treatment increased systemic translocation of C. albicans threefold in the heart. C. albicans also increased systemic distribution of the nanoparticles fivefold in the heart. Flow cytometric assays showed co-localization of the nanoparticles with epithelial cells, macrophages and dendritic cells. Nanoparticle-treated, C. albicans-infected mice exhibited induction of autophagy, ER stress, apoptosis, and inflammatory serum cytokines. C. albicans infection was associated with pyroptosis and suppressed expression of ER stress and apoptosis-related genes. Induction of apoptosis during nanoparticle treatment and in nanoparticle-treated-C. albicans infected mice was observed as DNA damage responses, mitochondrial depolarization and (Poly [ADP-Ribose] Polymerase) cleavage. C. albicans infection was associated with increased mRNA expression of anti-apoptotic genes. Both C. albicans infection and nanoparticle treatment showed enhanced chemoattraction of dendritic cells and polymorphonuclear cells to factors in vaginal washings in a chemotaxis assay. This study shows that both intravaginal treatment of mice with the nanoparticles and infection with C. albicans induce cytotoxic and inflammatory responses. C. albicans also suppressed cell apoptosis. These results clarify our understanding of how nanoparticles modulate host cellular responses during C. albicans infection and will be applicable for future research and development of intravaginal nanomedicines.
在最近的一项研究中，我们使用体外模型研究了酵母菌感染期间阴道内纳米颗粒暴露情况，结果表明，白色念珠菌暴露抑制了凋亡基因表达，并诱导阴道上皮细胞发生氧化应激和细胞焦亡。由聚（D，L-丙交酯-共-乙交酯）-（聚乙二醇）制成的穿透黏液的药物输送纳米颗粒通过单独激活细胞凋亡、内质网（ER）应激、氧化应激和 DNA 损伤修复反应，以及在某些情况下与白色念珠菌一起诱导细胞毒性。在本研究中，我们评估了荧光标记纳米颗粒在 CBA/J 小鼠体内的影响，这些小鼠先经阴道内挑战两小时，然后再用白色念珠菌阴道内挑战 18 小时。纳米颗粒处理使心脏中白色念珠菌的全身转移增加了三倍。白色念珠菌也使心脏中纳米颗粒的全身分布增加了五倍。流式细胞术分析显示纳米颗粒与上皮细胞、巨噬细胞和树突状细胞共定位。经纳米颗粒处理、白色念珠菌感染的小鼠表现出自噬、ER 应激、细胞凋亡和炎症性血清细胞因子的诱导。白色念珠菌感染与细胞焦亡和 ER 应激及细胞凋亡相关基因表达抑制有关。在纳米颗粒处理和纳米颗粒处理-白色念珠菌感染的小鼠中观察到的细胞凋亡诱导是由于 DNA 损伤反应、线粒体去极化和（多聚（ADP-核糖）聚合酶）裂解。白色念珠菌感染与抗凋亡基因的 mRNA 表达增加有关。白色念珠菌感染和纳米颗粒处理都显示出对阴道冲洗液中趋化因子的树突状细胞和多形核白细胞的趋化作用增强，在趋化试验中。本研究表明，阴道内给予小鼠纳米颗粒治疗和白色念珠菌感染都会引起细胞毒性和炎症反应。白色念珠菌还抑制细胞凋亡。这些结果阐明了我们对纳米颗粒在白色念珠菌感染期间如何调节宿主细胞反应的理解，将适用于未来阴道内纳米药物的研究和开发。
