Experimental Mouse Models of Disseminated Candida auris Infection
Experimental Mouse Models of Disseminated Candida auris Infection
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DOI：
10.1128/msphere.00339-19
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Eberle, Karen
中科院分区：
文献类型：
--
作者：
Xin, Hong;Mohiuddin, Farhan;Eberle, Karen
播散性念珠菌病是一种危及生命的疾病，并且仍然是美国住院患者最常见的血液感染。尽管有现代抗真菌疗法，但过去十年的粗死亡率仍然高得令人无法接受。特别是，耳念珠菌是一种具有多重耐药性、与医疗保健相关的真菌病原体，最近已成为第一种对全球公共卫生造成威胁的真菌病原体。因此，需要一个可靠的传播性耳念珠菌病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，我们建立了近交 A/J 静脉模型作为人类播散性耳念珠菌感染的合适模型。我们发现 A/J 小鼠中 C5 缺乏会导致复杂的表型，其特征是靶器官中真菌快速增殖，并产生独特且快速致命的反应。相比之下，C57BL/6J 小鼠和缺乏中性粒细胞弹性蛋白酶 (NE-/-) 的小鼠即使在环磷酰胺 (CY) 诱导的免疫抑制下，也能在高剂量耳念珠菌静脉注射攻击下存活下来。我们的研究首次深入了解了 C5 在宿主对耳念珠菌侵袭性感染反应中的作用，并建立了系统性耳念珠菌感染的近交 A/J 小鼠模型，而没有 CY 诱导的免疫抑制。 重要性 在过去的十年中，耳念珠菌作为一种多重耐药真菌病原体在全球范围内出现。尽管耳念珠菌最初是从外耳道中分离出来的，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错误识别、多真菌耐药率高以及患者死亡率高得令人无法接受而造成的持续挑战。本研究对侵入性耳念珠菌感染的特定遗传缺陷小鼠模型中的耳念珠菌毒力进行了评估，这有助于我们对宿主对耳念珠菌感染的防御知之甚少，这有望成为研究耳念珠菌侵入性感染发病机制、探索真菌引起的免疫反应、评估可能诱导感染免疫力的模型，并针对抗真菌疫苗的候选者。
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, Candida auris 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 C. auris 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 C. auris 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 C. auris 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 C. auris invasive infection and establishes an inbred A/J mouse model of systemic C. auris infection without CY-induced immunosuppression.IMPORTANCE In the last decade, Candida auris has emerged globally as a multidrug- resistant fungal pathogen. Although C. auris 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 mis-identification, high rates of multifungal drug resistance, and unacceptably high patient mortality. The assessment of C. auris virulence in a specific genetic deficiency mouse model of invasive C. auris infection in this study contributes to the little knowledge of host defense to C. auris infection, which holds promise as a model for investigating the pathogenesis of C. auris 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.