Candida Albicans Gastrointestinal Colonization and Dissemination

白色念珠菌胃肠道定植和传播

• 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
• 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

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.

侵袭性疾病需要白色念珠菌(CA)定植。成年小鼠对CA有抵抗力 胃肠道(GI)定植。我们已经鉴定出两种基因上截然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。这些厌氧共生体 诱导宿主免疫效应物(转录因子HIF1-α和抗菌肽CRAMP/LL-37) 显著降低CA GI定植。通过药物诱导HIF1-α和抽筋，我们 能够显著减少CA的定植，并将CA传播的死亡率降低50%。有趣的是， 能够从肠道中排出CA的厌氧细菌具有产生短链脂肪酸的能力 (SCFA)。单链脂肪酸已被证明具有多种免疫调节特性。因此，我的中央 假设肠道共生厌氧菌产生的单链脂肪酸是维持CA所必需的 殖民抵抗。这项工作将涉及两个具体目标。首先，我将确定SCFA是否 是抵抗CA定植所必需的。我会评估共生厌氧菌类杆菌 不能单独产生单链脂肪酸或单链脂肪酸的突变体可以减少CA的定植。我预测 单链脂肪酸是维持CA侵染抗性所必需的。其次，我将确定HIF-1α和/或 痉挛对于SCFA诱导的胃肠道定植减少是必要的。我会评估SCFA是否可以 促进人和小鼠肠上皮细胞对CA的清除及减少HIF1a对CA的定植 和Cramp基因敲除小鼠。我预测HIF1-α和JAMP是维持CA定植所必需的 抵抗。鉴于侵袭性真菌感染的高发病率和高死亡率，有限的武器库 抗真菌抗生素的出现，以及抗生素耐药菌株的不断出现，新的方法 治疗和预防患者的侵袭性真菌感染是迫切需要的。利用自然发生 厌氧细菌代谢物(SCFAs)增强胃肠道黏膜免疫效应以减少真菌定植 最终，减少传播可能代表着我们预防/治疗真菌方式的范式转变 病人中的感染。这些研究将为以下创新奠定基础：1)小说 单链脂肪酸激活肠道免疫防御以维持CA定植抗性的机制；2)一种新的 抑制CA传播的方法(SCFAs)；以及3)预防真菌感染的新方法 病人。总而言之，这些研究应该会导致对细菌/真菌相互作用的基本见解 并将为抗击人类宿主侵袭性真菌疾病提供新的视角。