Host factors affecting susceptibility to Candida auris.

影响耳念珠菌易感性的宿主因素。

• 批准号: 10015521
• 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/10015521
• 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 Merit 研究项目旨在通过新兴的多药来定义与粘膜感染相关的宿主因素 抗性人类真菌病原体，耳念珠菌 大多数人类真菌感染是由念珠菌属引起的。 常见的是白色念珠菌，它寄居在大约一半的健康成年人中，可能会发生病理性过度生长。 对共生微生物群或宿主免疫力的干扰通常仅限于粘膜表面。 念珠菌引起的血液感染在医疗机构中很常见，并且与高感染率相关。 最近，高毒力的耳念珠菌菌株已成为一种重要的医疗保健相关菌株。 这种酵母菌特别令人担忧，因为它经常传播到多个国家。 对常用的抗真菌药物具有耐药性，某些菌株对所有当前可用的抗真菌药物类别均表现出耐药性 截至 2019 年 6 月，耳念珠菌临床病例数量不断增加。 美国已有 700 多例确诊病例。令人担忧的是，医疗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被耳念珠菌定殖，显示出广泛传播的潜力 目前，VA 机构中刚刚开始发现耳念珠菌疫情。 基于高危患者（老年人、免疫抑制患者、ICU 或疗养院居民）的人口统计数据以及 由于这种病原体在美国迅速出现，这种新出现的念珠菌菌株的出现可能只是时间问题 为了开发有效的方法来预防传播，需要在退伍军人群体中更广泛地检测到。 迫切需要开展研究来阐明耳念珠菌在粘膜表面（包括口腔和口腔）定殖的倾向 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。 目前已开发出的耳念珠菌动物模型很少，目前还没有耳念珠菌的粘膜动物模型 我们开发了一种新的粘膜模型，其中耳念珠菌口腔和胃肠粘膜。 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确定宿主。 在这个项目中，我们计划改变包括免疫和微生物组特征在内的改变耳念珠菌易感性的因素。 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 我们将利用体外和体内的微生物组和先天免疫激活来感染耳念珠菌。 模型来定义影响耳念珠菌粘膜感染的关键先天免疫受体和途径。 许多感染耳念珠菌的患者之前曾接受过抗生素治疗其他感染，我们接下来将 确定抗生素引起的肠道和口腔微生物组变化对耳念珠菌感染的影响。 鉴于耳念珠菌多重耐药菌株的迅速出现，该项目具有非常重要的意义。 全球公共卫生威胁也可能影响退伍军人的健康，我们的项目将增进我们的了解。 研究这种病原体感染的免疫和系统危险因素，开发新的感染粘膜模型 研究微生物组对感染易感性的影响，我们的最终目标是帮助识别退伍军人和老年人。 其他感染风险最高的患者群体。