LSU Health Sciences Center New Orleans, New Orleans, Louisiana, USA
Loyola University New Orleans, New Orleans, Louisiana, USA.
mSphere. 2019 Sep 4;4(5):e00339-19. doi: 10.1128/mSphere.00339-19.
Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, crude mortality in the last decade has remained unacceptably high. In particular, is a multidrug-resistant, health care-associated fungal pathogen and has recently emerged as the first fungal pathogen to cause a global public health threat. A reliable animal model for disseminated candidiasis is therefore needed to study the unique aspects of this little-known host-pathogen interaction. In this study, we established an inbred A/J intravenous model as an appropriate model for human disseminated infection. We found that C5 deficiency in A/J mice results in a complex phenotype characterized by rapid fungal proliferation in target organs and the development of a unique and rapidly fatal response. In contrast, C57BL/6J mice and mice deficient in neutrophil elastase (NE) survived high-dose intravenous challenge, even with cyclophosphamide (CY)-induced immunosuppression. Our study is the first to provide insight into the role of C5 in the host responses to invasive infection and establishes an inbred A/J mouse model of systemic infection without CY-induced immunosuppression. In the last decade, has emerged globally as a multidrug-resistant fungal pathogen. Although was initially isolated from the external ear canal, it can cause outbreaks of invasive infections with very high mortality and comorbidities. Recent reports highlight the ongoing challenges due to organism misidentification, high rates of multifungal drug resistance, and unacceptably high patient mortality. The assessment of virulence in a specific genetic deficiency mouse model of invasive infection in this study contributes to the little knowledge of host defense to infection, which holds promise as a model for investigating the pathogenesis of invasive infection, exploring the immune responses elicited by the fungus, evaluating the possible induction of immunity to the infection, and targeting candidates for an antifungal vaccine.
播散性念珠菌病是一种危及生命的疾病，仍是美国住院患者中最常见的血流感染。尽管有现代抗真菌治疗方法，但过去十年的粗死亡率仍然高得不可接受。特别是， 是一种多药耐药的、与医疗保健相关的真菌病原体，最近已成为导致全球公共卫生威胁的第一种真菌病原体。因此，需要建立一种可靠的动物模型来研究这种鲜为人知的宿主-病原体相互作用的独特方面。在这项研究中，我们建立了一个近交 A/J 静脉内模型，作为人类播散性 感染的合适模型。我们发现 A/J 小鼠中的 C5 缺乏导致一种复杂的表型，其特征是靶器官中真菌的快速增殖和独特的快速致命反应的发展。相比之下，C57BL/6J 小鼠和缺乏中性粒细胞弹性蛋白酶 (NE) 的小鼠在高剂量 静脉内挑战后存活下来，即使在环磷酰胺 (CY) 诱导的免疫抑制下也是如此。我们的研究首次提供了关于 C5 在宿主对 侵袭性感染的反应中的作用的见解，并建立了一种没有 CY 诱导免疫抑制的近交 A/J 小鼠全身性 感染模型。在过去十年中， 已在全球范围内成为一种多药耐药的真菌病原体。虽然 最初是从外耳道分离出来的，但它可以引起侵袭性感染的爆发，死亡率和合并症非常高。最近的报告强调了由于生物体鉴定错误、多药耐药率高以及患者死亡率高得不可接受而导致的持续挑战。在这项研究中，评估侵袭性 感染的特定遗传缺陷小鼠模型中的 毒力有助于了解宿主对 感染的防御能力，这为研究 侵袭性感染的发病机制、探索真菌引起的免疫反应、评估对感染产生免疫的可能性以及针对抗真菌疫苗的候选物提供了希望。
