Host factors affecting susceptibility to Candida auris.

影响耳念珠菌易感性的宿主因素。

• 批准号: 10347167
• 负责人: Amy G Hise
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347167
• 关键词: Adult; Affect; Amphotericin B; Animal Model; Antibiotics; Antifungal Agents; Assisted Living Facilities; Azoles; Body Weight decreased; Candida; Candida albicans; Candida auris; Caregivers; Cell model; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Country; Data; Disease Outbreaks; Elderly; Epithelial Cells; Exhibits; Feces; Goals; Health; Health care facility; Healthcare; Hospitalization; Human; Immune; Immune response; Immunity; Immunologic Receptors; Immunosuppression; In Vitro; Indwelling Catheter; Infection; Inflammasome; Innate Immune Response; Integration Host Factors; Intestines; Long-Term Care; Microbe; Modeling; Mucous Membrane; Multi-Drug Resistance; Mus; Mycoses; Nursing Homes; Oral; Oral mucous membrane structure; Pathologic; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Population; Predisposition; Procedures; Public Health; Reporter; Reporting; Research; Research Project Grants; Resistance; Risk; Risk Factors; Sepsis; Severities; Surface; Time; Tissues; United States; Veterans; Virulent; Yeasts; base; cohort; commensal microbes; dectin 1; demographics; density; emerging pathogen; gastrointestinal; gut microbiome; health care settings; high risk; immune activation; immunosuppressed; in vitro Model; in vivo Model; infection risk; microbiome; microbiome alteration; mortality; mouse model; novel; oral microbiome; pathogen; pathogenic fungus; patient population; prevent; receptor; recruit; residence; resistant strain; screening; survival outcome; transmission process

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.

该VA优点研究项目旨在定义新兴的多药物与粘膜感染相关的宿主因素 抗性人类真菌病原体，念珠菌。大多数人类真菌感染是由念珠菌属引起的，是最多的 常见的是白色念珠菌，将大约一半的健康成年人定居。病理过度生长可能发生 对共生微生物群或宿主免疫学的扰动，通常仅限于粘膜表面。然而， 念珠菌属引起的血液感染。在医疗机构中很常见，并且与高率相关 死亡。最近，高度毒性菌株念珠菌已成为重要的医疗保健相关的 病原体已迅速传播到多个国家。这种酵母特别关注，因为它通常是 对常用抗真菌剂的耐药性，有些菌株对所有当前可用类别的抗性 抗真菌剂（即二唑，两性霉素B和echinocandins）。截至2019年6月，C. auris的临床病例数量增加 已经在美国报道了现在有700多个。令人震惊的是，筛查医疗机构的密切联系 表明其他患者和护理人员可以用C. Auris殖民，显示出宽度的潜力 在医疗机构中传播。目前，VA设施中刚开始发现C Auris爆发。 基于AT风险患者（老年人，免疫抑制，ICU或护士居民）的人口统计以及 这种病原体在美国的快速出现，这种新兴念珠菌的菌株可能只是时间问题 在退伍军人患者人群中发现了更广泛的检测。为了开发有效的方法以防止传播，有 迫切需要进行研究，以阐明甲状腺杆菌在包括口腔和包括口腔和 肠道并确定促进这种新兴病原体感染和过度生长的宿主因素。迄今为止， 几乎没有开发过Auris的动物模型，目前尚无粘膜粘膜粘膜模型 感染或定植。我们已经开发了一种新型的粘膜模型，在该模型中，Auris C. auris和胃肠道粘膜 观察到感染以及粪便中病原体的持续脱落。我们的总体研究目标是定义主机 包括免疫和微生物组谱的因素改变了对念珠菌的易感性。在这个项目中，我们计划 利用我们的口服和胃肠道感染模型来研究抗生素预曝光等因素的影响，改变 微生物组和天生的Auris感染后的先天免疫激活。我们将同时使用体外和体内 定义关键的先天免疫受体和影响念珠菌感染的关键先天免疫受体和途径。作为 许多感染了CA Auris的患者以前已经接受了抗生素治疗其他感染，我们将接下来 确定抗生素诱导的肠道和口服微生物组对念珠菌感染的影响。这 鉴于多毒的念珠菌抗菌菌株的快速出现，该项目非常重要 全球公共卫生威胁也可能影响退伍军人的健康。我们的项目将促进我们的理解 通过这种病原体感染的免疫和全身危险因素，发展了新型的感染粘膜模型和 研究微生物组对感染敏感性的影响。最终，我们的目标是帮助识别退伍军人和 其他患者人群感染风险最高。