Host factors affecting susceptibility to Candida auris.

这项VA Merit研究项目旨在确定与一种新出现的多种药物的粘膜感染相关的宿主因素 耐药的人类真菌病原体，金黄色念珠菌。大多数人类真菌感染是由念珠菌引起的，其中 常见的是白色念珠菌，它在大约一半的健康成年人中定居。病理性过度生长可发生在 对共生微生物区系或宿主免疫的扰动，通常仅限于粘膜表面。然而， 念珠菌引起的血液感染。在医疗保健环境中很常见，并与较高的 死亡率。最近，高毒力的金黄色念珠菌菌株已成为一种重要的保健相关菌株 已经迅速传播到多个国家的病原体。这种酵母特别令人担忧，因为它经常 对常用抗真菌药物产生抗药性，一些菌株对目前所有可用的类别都表现出抗药性 抗真菌药物(即唑类、两性霉素B和棘球菌素)。截至2019年6月，金黄色葡萄球菌临床病例数量不断上升 据报道，美国目前已有700多人感染。令人震惊的是，在卫生保健机构对密切接触者进行筛查 表明更多的患者和护理人员可以在奥氏杆菌中定居，显示出广泛传播的潜力。 在医疗保健环境中的传播。此时，在退伍军人管理局的设施中刚刚开始检测到C-Auris疫情。 根据高危患者(老年、免疫抑制、重症监护病房或疗养院居民)和 这种病原体在美国迅速出现，这种新出现的念珠菌菌株可能只是个时间问题 在退伍军人患者群体中更广泛地检测到。为了开发有效的方法来防止传播，有以下几点 迫切需要研究阐明金黄色葡萄球菌在包括口腔和口腔在内的粘膜表面定植的倾向 并确定促进这种新出现的病原体感染和过度生长的宿主因素。到目前为止， 目前已建立的耳蜗牛动物模型很少，目前尚无耳蜗牛粘膜动物模型。 感染或移居。我们开发了一种新的粘膜模型，在该模型中，金黄色葡萄球菌的口腔和胃肠粘膜 观察到感染以及病原体在粪便中的持续脱落。我们的总体研究目标是定义宿主 影响金黄色念珠菌易感性的因素包括免疫和微生物群组。在这个项目中，我们计划 利用我们的口腔和胃肠道感染模型来研究抗生素预暴露、改变等因素的影响 微生物组，以及感染金黄色葡萄球菌时的天然免疫激活。我们将利用体外和体内两种方式 确定影响金黄色念珠菌黏膜感染的关键先天免疫受体和途径的模型。AS 许多感染金黄色葡萄球菌的患者之前曾接受过抗生素治疗其他感染，我们接下来 确定抗生素引起的肠道和口腔微生物群改变对金黄色念珠菌感染的影响。这 鉴于多重耐药金黄色念珠菌菌株的迅速出现，该项目具有重要意义 世界范围的公共卫生威胁，也可能影响退伍军人的健康。我们的项目将增进我们的理解 研究感染这种病原体的免疫和系统危险因素，开发新的粘膜感染模型和 研究微生物群对感染易感性的影响。最终，我们的目标是帮助识别退伍军人和 感染风险最高的其他患者群体。

This VA Merit research project aims to define host factors associated with mucosal infection by an emerging multi-drug resistant human fungal pathogen, Candida auris. Most human fungal infections are caused by Candida spp, the most common being C. albicans which colonizes approximately half of healthy adults. Pathological overgrowth can occur with perturbations to the commensal microbiota or host immunity and is normally limited to mucosal surfaces. However, bloodstream infections due to Candida spp. are common in healthcare settings and are associated with a high rate of mortality. Recently, the highly virulent strain Candida auris has emerged as an important healthcare-associated pathogen that has rapidly disseminated to multiple countries. This yeast is particularly concerning because it is often resistant to commonly used antifungal agents, with some strains exhibiting resistance to all currently available classes of antifungals (i.e., azoles, amphotericin B, and echinocandins). As of June, 2019, a rising number of clinical cases of C. auris have been reported in the United States, now over 700. Alarmingly, screening of close contacts in health care facilities shows that additional patients and care givers can be colonized with C. auris, showing the potential for widespread dissemination in healthcare settings. At this time, C auris outbreaks have just started to be detected in VA facilities. Based on the demographics of at risk patients (elderly, immunosuppressed, ICU or nursing home residents) and the rapid emergence of this pathogen in the US, it is likely just a matter of time before this emerging strain of Candida is more widely detected in veteran patient populations. To develop effective approaches to prevent transmission, there is an urgent need for studies that clarify the propensity for C. auris to colonize mucosal surfaces including the oral and intestinal tracts and to identify host factors that promote infection and overgrowth of this emerging pathogen. To date, few animal models of C. auris have been developed and currently there are no mucosal animal models of C auris infection or colonization. We have developed a novel mucosal model in which C. auris oral and gastrointestinal mucosal infection is observed as well as persistent shedding of the pathogen in stool. Our overall research goal is to define host factors including immune and microbiome profiles that alter susceptibility to Candida auris. In this project we plan to utilize our models of oral and GI infection to investigate the impact of factors such as antibiotic pre-exposure, alterations of the microbiome, and innate immune activation on infection with C. auris. We will utilize both in vitro and in vivo models to define critical innate immune receptors and pathways that impact mucosal infection with Candida auris. As many patients who are infected with C auris have previously received antibiotics to treat other infections, we will next determine the impact of antibiotic-induced alterations of the gut and oral microbiome on Candida auris infection. This project is highly significant given the rapid emergence of multi-drug resistant strains of Candida auris which poses a world-wide public health threat that also will likely impact Veteran’s health. Our project will advance our understanding of immune and systemic risk factors for infection with this pathogen, develop novel mucosal models of infection and study the impact of the microbiome on susceptibility to infection. Ultimately our goal is to help identify Veteran and other patient populations at highest risk for infection.