DataSheet_1_Significant Differences in Host-Pathogen Interactions Between Murine and Human Whole Blood.pdf

Murine infection models are widely used to study systemic candidiasis caused by C. albicans. Whole-blood models can help to elucidate host-pathogens interactions and have been used for several Candida species in human blood. We adapted the human whole-blood model to murine blood. Unlike human blood, murine blood was unable to reduce fungal burden and more substantial filamentation of C. albicans was observed. This coincided with less fungal association with leukocytes, especially neutrophils. The lower neutrophil number in murine blood only partially explains insufficient infection and filamentation control, as spiking with murine neutrophils had only limited effects on fungal killing. Furthermore, increased fungal survival is not mediated by enhanced filamentation, as a filament-deficient mutant was likewise not eliminated. We also observed host-dependent differences for interaction of platelets with C. albicans, showing enhanced platelet aggregation, adhesion and activation in murine blood. For human blood, opsonization was shown to decrease platelet interaction suggesting that complement factors interfere with fungus-to-platelet binding. Our results reveal substantial differences between murine and human whole-blood models infected with C. albicans and thereby demonstrate limitations in the translatability of this ex vivo model between hosts.

小鼠感染模型（murine infection models）被广泛应用于探究白色念珠菌（C. albicans）引发的全身性念珠菌病。全血模型（whole-blood models）可用于阐明宿主-病原体相互作用（host-pathogens interactions）机制，目前已被应用于人血中多种念珠菌属物种的相关研究。本研究将人源全血模型适配至小鼠血液体系。与人类血液不同，小鼠血液无法有效降低真菌负荷（fungal burden），且可观察到白色念珠菌发生更为显著的菌丝形成（filamentation）。该现象与白细胞（leukocytes，尤其是中性粒细胞（neutrophils））对真菌的结合率降低相吻合。小鼠血液中中性粒细胞数量偏少仅能部分解释其无法有效控制感染与菌丝形成的原因：补充外源小鼠中性粒细胞仅能对真菌杀伤产生有限的改善效果。此外，真菌存活率提升并非由菌丝形成增强所介导，因为菌丝形成缺陷型突变株同样无法被有效清除。本研究还观察到血小板与白色念珠菌的相互作用存在宿主依赖性差异：小鼠血液中血小板的聚集、黏附与活化水平均显著升高。已有研究表明，人血中的调理作用（opsonization）会降低血小板与真菌的相互作用，提示补体因子（complement factors）会干扰真菌与血小板的结合。本研究结果揭示了感染白色念珠菌的小鼠与人类全血模型之间存在显著差异，从而证实了该离体模型（ex vivo model）在不同宿主间的转化应用存在局限性。