Antifungal immunity controlled by commensal intestinal bacteria.

由肠道共生细菌控制的抗真菌免疫。

• 批准号: 9236190
• 负责人: Tianlun Tony Jiang
• 金额: $ 3.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236190
• 关键词: Address; Antibiotic Therapy; Antibiotics; Antifungal Agents; Antigens; Bacteria; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candida albicans; Cell Differentiation process; Cells; Defect; Disseminated candidiasis; Dose; Engineering; Enteral; Enterobacteriaceae; Epithelial Cells; Family; Hematopoietic; Homeostasis; Host Defense; Human; Hyphae; Immune; Immunity; Impairment; Infection; Influenza A virus; Interleukin-17; Intestines; Knowledge; Ligands; Lipopolysaccharides; Lymphocytic choriomeningitis virus; MHC Class II Genes; Mediating; Microbe; Modeling; Molecular; Mus; Mycoses; Neutrophil Infiltration; Pathogenicity; Peptides; Play; Predisposition; Production; Property; Recombinants; Role; Specificity; Symbiosis; TLR4 gene; Time; Tissues; Viral; Virus; Virus Diseases; antiviral immunity; base; commensal microbes; cytokine; density; experimental study; improved; innovation; microbial community; mortality; neutrophil; pathogen; public health relevance; reconstitution; rectal; transcription factor

 DESCRIPTION (provided by applicant): Commensal intestinal microbes are now increasingly recognized to control systemic immune homeostasis and responsiveness. The greatest density of commensal bacteria reside within the intestinal lumen, and accumulating evidence shows these microbial communities play pivotal roles during infection with more pathogenic microbes. Studies using model viral pathogens to probe host defense shifts following antibiotic induced eradication of commensal enteric bacteria consistently show blunted expansion of protective virus specific CD8+ T cells that parallels increased susceptibility to viral infections. Interestinly, these immune modulatory benefits of commensal bacteria appear restricted to viral pathogens since our initial studies show commensal intestinal bacteria simultaneously impair host defense against disseminated infection with the human fungal pathogen, Candida albicans. Antibiotic induced eradication of commensal enteric bacteria accelerates C. albicans fungal clearance and improves host survival by unleashing more robust and sustained expansion of neutrophils. However, in addition to neutrophils, other protective antifungal adaptive immune components are also likely unleashed by depletion of commensal bacteria since differences in fungal pathogen burden and survival are only appreciated during later time points after infection (days 10-20), yet conspicuously absent at early post-infection time points (day 5) before adaptive immune components are fully engaged. In particular, the accelerated expansion and more efficient mobilization of neutrophils after antibiotic induced eradication of intestinal bacteria strongly suggests IL-17 producing (Th17) CD4+ T cells as the likely adaptive component responsible for these protective shifts in antifungal immunity. These findings form the scientific premise for our overall hypothesis that commensal enteric bacteria dampen the priming and differentiation of fungal-specific Th17 CD4+ T cells that promote antifungal immunity through IL-17 production. Furthermore, given the potent ability whereby the TLR4 ligand, lipopolysaccharide, restores susceptibility to disseminated C. albicans infection in a dose dependent fashion when administered intra-rectally to commensal bacteria eradicated mice, our secondary hypothesis is that shifts in systemic immune cell responsiveness that control antifungal immunity is dependent on intestinal recognition of commensal bacteria through toll-like receptor 4 (TLR4). These innovative hypotheses will be addressed with the following specific aims: (1) Identify shifts in C. albicans fungal-specific CD4+ T cell priming controlled by intestinal commensal bacteria; (2) Investigate the necessity for TLR4 in commensal enteric bacteria mediated susceptibility to systemic C. albicans infection; (3) Determine the contribution of commensal bacteria stimulation through TLR4 among intestinal epithelial cells compared with hematopoietic immune cells in controlling antifungal immunity. Successful completion of these studies will establish the molecular and cellular immune mechanisms whereby commensal enteric bacteria control systemic antifungal immunity.

 描述（由申请人提供）：现在越来越多地认识到肠道共生微生物控制全身免疫稳态和反应性。肠道细菌的最大密度存在于肠腔中，越来越多的证据表明，这些微生物群落在感染更多病原微生物期间起着关键作用。使用模型病毒病原体来探测抗生素诱导的肠道细菌根除后宿主防御转变的研究一致地显示保护性病毒特异性CD8 + T细胞的钝化扩增，其与对病毒感染的易感性增加平行。此外，肠道细菌的这些免疫调节益处似乎仅限于病毒病原体，因为我们的初步研究表明，肠道细菌同时损害宿主对人类真菌病原体白色念珠菌播散性感染的防御。抗生素诱导的肠道细菌根除加速了C。白色念珠菌真菌清除，并通过释放更强大和持续的中性粒细胞扩增来提高宿主存活率。然而，除了嗜中性粒细胞之外，其他保护性抗真菌适应性免疫组分也可能通过消耗肠道细菌而释放，因为真菌病原体负荷和存活的差异仅在感染后的较晚时间点（第10 - 20天）期间被理解，而在适应性免疫组分完全参与之前的感染后早期时间点（第5天）明显不存在。特别是，在抗生素诱导的肠道细菌根除后，嗜中性粒细胞的加速扩增和更有效的动员强烈表明产生IL-17的（Th17）CD4 + T细胞可能是抗真菌免疫中这些保护性转变的适应性成分。这些发现形成了我们的总体假设的科学前提，即肠道细菌抑制真菌特异性Th17 CD4 + T细胞的启动和分化，通过IL-17的产生促进抗真菌免疫。此外，考虑到TLR4配体脂多糖恢复对播散性C.当直肠内给药于肠道细菌根除的小鼠时，以剂量依赖性方式观察到白色念珠菌感染，我们的次要假设是控制抗真菌免疫的全身免疫细胞反应性的变化依赖于肠道通过Toll样受体4（TLR4）对肠道细菌的识别。这些创新的假设将被解决与以下具体目标：（1）确定变化的C。白念珠菌真菌特异性CD4 + T细胞引发控制 （2）探讨TLR4在大肠杆菌介导系统性C.白色念珠菌感染;（3）确定肠道细菌通过TLR4刺激肠上皮细胞与造血免疫细胞在控制抗真菌免疫中的贡献。这些研究的成功完成将建立肠道细菌控制全身抗真菌免疫的分子和细胞免疫机制。