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：
9761967
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/9761967
关键词：
16S ribosomal RNA sequencing Adult Anaerobic Bacteria Animals Antibiotic Resistance Antibiotics Antifungal Antibiotics Bacteria Bacterial Infections Bacteroides Candida albicans Chemicals Clinical Data Development Disease Epithelial Cells Fostering Future 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 Mucous Membrane Mus Muscle Cramp Mycoses Neonatal Operative Surgical Procedures Organ Patients Pharmacology Play Population Process Production Property Proteins Resistance Risk Role Sepsis Stem cell transplant Tissues Transplant Recipients Treatment Cost Volatile Fatty Acids Work antimicrobial antimicrobial peptide cancer cell candidemia chemotherapy colonization resistance combat commensal bacteria gastrointestinal gastrointestinal epithelium gut colonization gut microbiota hypoxia inducible factor 1 immunoregulation innovation insight microbial microbiota mortality mouse model mutant neonatal patient novel novel strategies pathogenic bacteria pathogenic fungus 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) 定植是成年小鼠对 CA 具有抵抗力所必需的。我们已经鉴定出两种遗传上不同的厌氧共生细菌。可以单独维持无菌小鼠的 CA 定植抵抗力。诱导宿主免疫效应物（转录因子 HIF1-α 和抗菌肽 CRAMP/LL-37）通过药理学诱导 HIF1-α 和 CRAMP，我们显着减少了 CA GI 定植。能够显着减少 CA 定植并将 CA 传播造成的死亡率降低 50%。可以将 CA 从肠道中排出的厌氧细菌具有产生短链脂肪酸的能力（SCFA）已被证明具有多种免疫调节特性。假设肠道共生厌氧菌产生的 SCFA 是维持 CA 所必需的这项工作将涉及两个具体目标，首先，我将确定 SCFA 是否是。我将评估是否存在共生厌氧拟杆菌。我预测不能产生 SCFA 或单独 SCFA 的 thetaiotamicron 突变体可以减少 CA 定植。 SCFA 对于维持 CA 定植抵抗是必需的。其次，我将确定是否是 HIF-1α 和/或。 CRAMP 对于 SCFA 诱导的胃肠道定植减少是必要的，我将评估 SCFA 是否可以。促进培养的人和小鼠肠道上皮细胞中的 CA 清除，并减少 Hif1a 中的 CA 定植和 Cramp 敲除小鼠，我预测 HIF1-α 和 CRAMP 对于维持 CA 定植是必需的。鉴于与侵袭性真菌感染相关的高发病率和死亡率，有限的武器库。抗真菌抗生素的使用，以及抗生素耐药菌株的不断出现，新的方法迫切需要利用自然发生的方法来治疗和预防患者的侵袭性真菌感染。厌氧细菌代谢物 (SCFA) 增强胃肠道粘膜免疫效应，减少真菌定植最终减少传播可能代表我们预防/治疗真菌方式的范式转变这些研究将为以下创新奠定基础：1）一种新颖的方法。 SCFA 激活肠道免疫防御以维持 CA 定植抵抗的机制 2) 一种新颖的机制；抑制 CA 传播的方法（SCFA）；以及 3）预防真菌感染的新方法总之，这些研究应该能够对细菌/真菌的相互作用产生基本的了解。肠道，将为对抗人类宿主的侵袭性真菌病提供新的视角。