Candida Albicans Gastrointestinal Colonization and Dissemination

白色念珠菌胃肠道定植和传播

基本信息

批准号：
9360089
负责人：
ANDREW Y KOH
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-28 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360089
关键词：
Adult Anaerobic Bacteria Animals Antibiotic Resistance Antibiotics Antifungal Antibiotics Bacteria Bacterial Infections Bacteroides Candida albicans Chemicals Clinical Data Development Disease Epithelial Cells Fostering Future Gastrointestinal tract structure Genes Germ-Free Goals Grant Homeostasis Human Hypoxia Inducible Factor Immune Immunocompromised Host Individual Infection Intestines Knockout Mice Laboratories Lead Length of Stay Malignant Neoplasms Modeling Molecular Monitor Morbidity - disease rate Mus Muscle Cramp Mycoses Neonatal Operative Surgical Procedures Organ Patients Pharmacology Play Population Process Production Property Proteins Resistance Risk Role Sepsis Stem cell transplant Symbiosis Tissues Transplant Recipients Treatment Cost Volatile Fatty Acids Work antimicrobial antimicrobial peptide candidemia chemotherapy combat commensal microbes gastrointestinal gastrointestinal epithelium gut microbiota hypoxia inducible factor 1 immunoregulation innovation insight killings microbial microbiota mortality mouse model mutant neonatal patient novel novel strategies pathogen pathogenic bacteria prevent resistant strain targeted treatment transcription factor

项目摘要

Candida albicans (CA) colonization is required for invasive disease. Adult mice are resistant to CA gastrointestinal (GI) colonization. We have identified two genetically distinct anaerobic commensal bacteria that can individually maintain CA colonization resistance in germ-free mice. These anaerobic commensals induce host immune effectors (transcription factor, HIF1-α, and antimicrobial peptide, CRAMP/LL-37) that significantly decrease CA GI colonization. By pharmacologically inducing both HIF1-α and CRAMP, we were able to significantly reduce CA colonization and reduce mortality from CA dissemination by 50%. Interestingly, the anaerobic bacteria that can expel CA from the gut share the ability to produce short-chain fatty acids (SCFAs). SCFAS have been shown to have numerous immunomodulatory properties. Therefore, my central hypothesis is that SCFAs produced by gut commensal anaerobic bacteria are necessary to maintain CA colonization resistance. This work will involve two specific aims. First, I will determine whether SCFAs are necessary for CA colonization resistance. I will evaluate whether commensal anaerobe Bacteroides thetaiotamicron mutants unable to produce SCFAs or SCFAs alone can reduce CA colonization. I predict that SCFAs are necessary for maintaining CA colonization resistance. Second, I will determine if HIF-1α and/or CRAMP are necessary for SCFA-induced GI colonization reduction. I will evaluate whether SCFAs can promote CA clearance in cultured human and mouse gut epithelial cells and CA colonization reduction in Hif1a and Cramp knockout mice. I predict that HIF1-α and CRAMP are necessary for maintaining CA colonization resistance. Given the high morbidity and mortality associated with invasive fungal infections, the limited arsenal of antifungal antibiotics, and the continuing emergence of antibiotic resistant strains, new approaches to treating and preventing invasive fungal infections in patients are desperately needed. Using natural occurring anaerobic bacterial metabolites (SCFAs) to boost GI mucosal immune effectors to reduce fungal colonization and ultimately decrease dissemination could represent paradigm shift in the way we prevent/treat fungal infections in patients. These studies will lay the groundwork for the following innovations: 1) a novel mechanism by which SCFAs activate gut immune defenses to maintain CA colonization resistance; 2) a novel approach (SCFAs) to inhibit CA dissemination; and 3) a novel approach to preventing fungal infections in patients. Together, these studies should lead to fundamental insights into bacterial/fungal interactions within the intestinal tract and will provide new perspectives in combating invasive fungal disease in the human host.

白色念珠菌（CA）侵入性疾病需要定植。成年小鼠对CA具有抗性胃肠道（GI）定殖。我们已经确定了两个遗传上不同的厌氧共生细菌可以单独维持无菌小鼠的Ca定植抗性。这些厌氧分子诱导宿主免疫作用（转录因子，HIF1-α和抗菌肽，抽筋/LL-37）明显降低了CA GI定殖。通过药物诱导的HIF1-α和抽筋，我们是可以显着降低CA定植，并将CA传播的死亡率降低50％。有趣的是，可以从肠道中排出Ca的厌氧细菌具有产生短链脂肪酸的能力（SCFA）。 SCFA已显示具有许多免疫调节特性。因此，我的中心假设是肠道共生厌氧菌产生的SCFA对于维持Ca是必要的定殖抗性。这项工作将涉及两个具体目标。首先，我将确定SCFA是否是 Ca定植抗性所需的。我将评估共生的厌氧菌杆菌是否无法单独产生SCFA或SCFA的thetaiotamicron突变体可以减少CA定殖。我预测 SCFA对于维持CA定植耐药性是必要的。其次，我将确定是否HIF-1α和/或抽筋是SCFA诱导的GI定殖减少所必需的。我将评估SCFA是否可以在培养的人和小鼠肠道上皮细胞中促进CA清除，并在HIF1A中降低Ca定植和抽筋小鼠。我预测HIF1-α和抽筋对于维持Ca定植是必要的反抗。鉴于与侵入性真菌感染相关的高发病率和死亡率，阿森纳有限抗真菌抗生素以及抗生素抗性菌株的持续出现，新方法迫切需要治疗和预防患者的侵入性真菌感染。使用自然发生厌氧细菌代谢物（SCFAS）可增强胃肠道粘膜免疫作用以减少真菌定殖最终减少传播可能代表我们预防/治疗真菌的方式的范式转移患者感染。这些研究将为以下创新奠定基础：1）小说 SCFA激活肠道免疫防御以维持Ca定植抗性的机制； 2）小说方法（SCFA）抑制CA传播； 3）一种预防真菌感染的新方法患者。这些研究共同导致对细菌/真菌相互作用的基本见解肠道，将为打击人类宿主的侵入性真菌疾病提供新的观点。