Atherogenic role of T cell modulation by intestinal bacteria

肠道细菌调节 T 细胞的致动脉粥样硬化作用

• 批准号: 8442852
• 负责人: Debbie Beasley
• 金额: $ 18.92万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442852
• 关键词: Address; Anaerobic Bacteria; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Apolipoprotein E; Atherosclerosis; Autoimmune Diseases; Bacteria; Blood Vessels; CD4 Positive T Lymphocytes; Cause of Death; Cell Differentiation process; Cells; Cessation of life; Complex; Data; Detection; Development; Disease; Epithelial; Epithelial Cells; Exhibits; Exposure to; Functional disorder; Germ-Free; Goals; Grant; House mice; Housing; Human; Hygiene; Immune; Immune response; Immunology; In Vitro; Incidence; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-17; Intestines; Lesion; Link; Lymphatic System; Medical; Messenger RNA; Methods; Microbe; Morbidity - disease rate; Mus; Organism; Pathogenesis; Population; Predisposition; Prevalence; Process; Production; Proteins; Recruitment Activity; Regulatory T-Lymphocyte; Reproduction spores; Research; Research Personnel; Role; Secondary to; Serum; Shapes; Signal Transduction; Site; Small Intestines; Societies; Source; Staging; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Toll-Like Receptor 2; Universities; Validation; Vascular Diseases; Work; adaptive immunity; atherogenesis; base; commensal microbes; cost; disability; improved; innovation; interdisciplinary collaboration; microbial; mouse model; novel; pathogen; pathogen exposure; prevent; response; toll-like receptor 4

DESCRIPTION (provided by applicant): Atherosclerosis is a leading cause of death and morbidity in the US, and has complex, multifactorial pathophysiology. The goal of this exploratory grant is to determine whether intestinal colonization by specific commensal bacteria modulates T cell responses so as to promote atherosclerosis. The idea relies on key recent lines of evidence and our preliminary data. Colonization of the gut of mice by specific intestinal microbes promotes local differentiation of specific T cell subsets, including proinflammatory Th1 and Th17 cells, and anti-inflammatory regulatory T cells. Th17 cell differentiation within the gut is promoted by segmented filamentous bacteria (SFB), which are long Gram-positive spore-forming anaerobes that adhere tightly to small intestine epithelial cells. Because SFB promote Th17 differentiation, and Th17 cells are thought to exert an atherogenic role in apolipoprotein E-deficient (ApoE KO) mice, we hypothesize that intestinal SFB colonization increases susceptibility of ApoE KO mice to atherosclerosis. Our preliminary findings support this idea, because we found that serum IL-17 and splenic IL-17 mRNA levels were initially low in ApoE KO mice, but co-housing these mice with SFB-colonized mice led to their increased incidence of small intestinal SFB accompanied by increased levels of serum IL-17, splenic IL-17 mRNA, and splenocytic IL-17 release in vitro. Our working hypothesis is that colonization of the small intestine by SFB promotes development within the intestinal wall of IL-17-expressing T cells, which are then mobilized into the lymphatic system and recruited to sites of aortic inflammation, where they act locally by producing IL-17 and IFN-?, which synergistically promote atherogenesis. Based on preliminary findings that Toll-like receptor-4 (TLR4)-deficient mice have increased abundance of intestinal SFB, we also hypothesize that TLR4 signaling can limit intestinal SFB colonization in ApoE KO mice. The specific aims are to determine whether 1) colonization of the small intestine of ApoE KO mice by SFB drives local induction of small intestinal, systemic, and intralesional Th17 cell populations, and thereby promotes aortic lesion formation; and 2) TLR4-dependent intestinal expression of antibacterial proteins inhibits intestinal colonization with SFB in ApoE KO mice with low levels of SFB exposure. This exploratory project will test the novel concept that a specific bacterium that resides in the gut, previously thought to be non-pathogenic, promotes atherogenesis. Validation of this idea will potentially alter the drivers of atherosclerosis research. The project will establish and exploit a new interdisciplinary collaboration between established vascular (Dr. Beasley) and immunology (Dr. Huber) researchers at Tufts University. We will capitalize upon innovative and highly sensitive detection methods for early-stage atherogenesis and bacteria within a relevant animal model, to optimize long-term translational potential.

描述（由申请人提供）：动脉粥样硬化是美国死亡和发病的主要原因，具有复杂的多因素病理生理学。这项探索性资助的目的是确定特定共生菌的肠道定植是否调节T细胞反应从而促进动脉粥样硬化。这个想法依赖于最近的关键证据线和我们的初步数据。特定肠道微生物在小鼠肠道的定植促进了特定T细胞亚群的局部分化，包括促炎Th1和Th17细胞以及抗炎调节性T细胞。肠道内的Th17细胞分化由分节丝状细菌（SFB）促进，SFB是紧密粘附在小肠上皮细胞上的革兰氏阳性长芽孢厌氧菌。由于SFB促进Th17分化，而Th17细胞被认为在载脂蛋白e缺陷（ApoE KO）小鼠中发挥致动脉粥样硬化作用，我们假设SFB在肠道中的定植增加了ApoE KO小鼠对动脉粥样硬化的易感性。我们的初步研究结果支持这一观点，因为我们发现ApoE KO小鼠的血清IL-17和脾脏IL-17 mRNA水平最初较低，但将这些小鼠与SFB定植的小鼠共同饲养导致小肠SFB发病率增加，同时体外血清IL-17、脾脏IL-17 mRNA水平和脾细胞IL-17释放水平增加。我们的工作假设是，SFB在小肠的定植促进了表达IL-17的T细胞在肠壁内的发育，然后这些T细胞被动员到淋巴系统并招募到主动脉炎症部位，在那里它们通过产生IL-17和IFN-？，协同促进动脉粥样硬化。基于toll样受体-4 （TLR4）缺陷小鼠肠道SFB丰度增加的初步发现，我们也假设TLR4信号可以限制ApoE KO小鼠肠道SFB的定植。具体目的是确定1)SFB在ApoE KO小鼠小肠的定植是否驱动小肠、全身和病灶内Th17细胞群的局部诱导，从而促进主动脉病变的形成；2)在低水平SFB暴露的ApoE KO小鼠中，tlr4依赖性肠道抗菌蛋白表达抑制SFB在肠道的定植。这个探索性项目将测试一个新的概念，即一种特定的细菌存在于肠道中，以前被认为是非致病性的，促进了动脉粥样硬化的发生。这一观点的验证将有可能改变动脉粥样硬化研究的驱动因素。该项目将建立和开发一个