McFadden Michael J, Anku Juliet A E, Davis Faith A, O'Meara Teresa R
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
bioRxiv. 2025 Jun 2:2025.06.02.657403. doi: 10.1101/2025.06.02.657403.
is a growing public health concern, capable of causing long-term contamination of healthcare settings, skin colonization, and life-threatening bloodstream infections. However, pathogenesis is not well understood, which is exacerbated by limitations and discrepancies in existing animal infection models. Further, the effects of growth phase on virulence have not been examined, despite growth phase being linked to virulence in many bacterial species. To address this question, and to develop an immunocompetent murine model of infection, we directly compared log and stationary phase systemic infection in immunocompetent C57BL/6J mice at high and low doses of infection. Systemic infection with high dose log-phase results in rapid mortality between 2 hours and 1 day post infection, whereas stationary phase results in significantly extended survival. However, at low doses of infection, there was no difference in mortality kinetics between log and stationary phase cells. We observed that initially colonizes multiple organs but is rapidly cleared from the lungs and spleen, while kidney fungal burdens remain stable. Decreased fibrinogen levels and blood clotting in the lungs of mice infected with high dose log-phase suggest that blood clotting may drive rapid mortality, potentially associated with increased β-glucan exposure and mannan abundance observed in log phase . These results will inform the development of a more standardized animal model of systemic infection, which can be used to reveal key aspects of pathogenesis.
是一个日益严重的公共卫生问题，能够导致医疗机构的长期污染、皮肤定植以及危及生命的血流感染。然而，其发病机制尚未完全明确，现有动物感染模型的局限性和差异加剧了这一情况。此外，尽管生长阶段与许多细菌种类的毒力相关，但尚未研究生长阶段对毒力的影响。为了解决这个问题，并建立一个具有免疫活性的小鼠感染模型，我们在免疫活性的C57BL/6J小鼠中，以高剂量和低剂量感染直接比较了对数期和稳定期的全身感染情况。高剂量对数期的全身感染导致感染后2小时至1天内迅速死亡，而稳定期则导致显著延长的生存期。然而，在低剂量感染时，对数期和稳定期细胞之间的死亡动力学没有差异。我们观察到最初定殖于多个器官，但很快从肺和脾中清除，而肾脏真菌负荷保持稳定。高剂量对数期感染的小鼠肺中纤维蛋白原水平降低和血液凝固表明，血液凝固可能导致快速死亡，这可能与对数期观察到的β-葡聚糖暴露增加和甘露聚糖丰度增加有关。这些结果将为更标准化的全身感染动物模型的开发提供信息，该模型可用于揭示发病机制的关键方面。
