Tick Gut Immunome- Gut Microbiota Interactions in the Context of Tick-Borne Pathogens

蜱虫肠道免疫组-蜱传病原体背景下肠道微生物群的相互作用

• 批准号: 10222519
• 负责人: Erol Fikrig
• 金额: $ 41.88万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222519
• 关键词: Anaplasma; Anaplasma phagocytophilum; Attention; Bacteria; Black-legged Tick; Borrelia; Borrelia burgdorferi; Cell membrane; Cells; Conflict (Psychology); Data; Glycoproteins; Goals; Homeostasis; Immune; Immune response; Immune signaling; Impairment; Individual; Infection; Infection Control; Interferons; Life Cycle Stages; Lipids; Microbe; Molecular; Mus; Pathway interactions; Physiology; Prevalence; RNA Interference; Research; Research Design; Role; Salivary Glands; Signal Pathway; Signal Transduction; Structure; Ticks; Toxin; Work; axenic culture; base; co-infection; cytokine; defense response; dysbiosis; experimental study; feeding; gastrointestinal epithelium; gut colonization; gut microbiome; gut microbiota; human disease; in silico; insight; knock-down; microbiota; novel; pathogen; reconstitution; response; tick feeding; tick-borne pathogen; transcription factor

PROJECT 3 - Abstract This proposal will determine the influence of tick gut microbiota on tick gut immune signaling pathways JAK/STAT and IMD and the functional consequence on Borrelia burgdorferi, and Anaplasma phagocytophilum survival in the tick - an important determinant of infection prevalence. Our earlier work (Narasimhan et al, Cell Host Microbe 15:58-71, 2014) and our recent work (Abraham et al, Proc Natl Acad Sci,114: E781-790, 2017) demonstrate that tick gut microbiota modulates B. burgdorferi colonization and A. phagocytophilum infection of Ixodes scapularis. Perturbation of the gut microbiota (dysbiosis) disrupts the integrity of the peritrophic matrix - an acellular glycoprotein-rich layer that separates the gut epithelium from the lumen. While B. burgdorferi resides on the gut epithelium and an intact peritrophic matrix (PM) affords protection from toxic components in the tick gut enhancing their colonization of the gut, A. phagocytophilum circumvents the PM barrier to infect the gut and finally the salivary glands by as-yet-unknown mechanisms and exploits a compromised PM to efficiently breach the PM barrier. These observations reveal a novel and apparently contrasting facet of Borrelia-tick and Anaplasma-tick interactions. In a more recent effort (Narasimhan et al, Nat Commun. 184: s41467, 2017), we draw attention to the dynamic interactions of the tick microbiota with tick gut defense responses and to the diverse ways in which tick microbiota might influence pathogen survival in the tick gut. These findings, together with the observations of Projects 1 and 2 emphasize the influence of the interactions between tick gut microbiota- and immune responses on pathogen survival in the tick. In Aim 1 we will characterize the extent to which gut microbiota interacts with tick gut immune responses (specifically JAK/STAT and IMD) and host cytokines (specifically IFN) that enter the tick gut, and define gut bacterial profiles that are significantly influenced by the tick and host immune responses and vice-versa. In Aim 2 we will reconstitute specific gut microbiota or bacterial components and determine how this influences tick gut immune signaling and ultimately the survival of B. burgdorferi or A. phagocytophilum in the tick This research endeavor will unfold a mechanistic understanding of the functional consequence of tick gut microbiota on tick gut immune signaling and the survival of two important tick-borne pathogens that cause human disease.

项目3-摘要 该提案将确定tick肠肠菌对tick肠免疫的影响 信号通路JAK/STAT和IMD以及对Borrelia Burgdorferi的功能后果， 和滴答虫的吞噬吞噬细胞生存 - 感染的重要决定因素 流行率。我们的早期工作（Narasimhan等人，细胞宿主微生物15：58-71，2014）和我们最近的工作 （Abraham等人，Proc Natl Acad Sci，114：e781-790，2017）证明了tick肠菌调节 B. burgdorferi定植和ixodes肩cap虫感染的吞噬细胞感染。肠扰动 微生物群（营养不良）破坏了营养基质的完整性 - 富含糖蛋白的含量 这将肠道上皮与管腔分开。而B.b。brgdorferi住宅在肠道上皮和 完整的营养基质（PM）可保护tick肠中的有毒成分增强其 肠道的定植，吞噬细胞嗜酸杆菌绕过PM屏障以感染肠道，最后 唾液腺通过尚未尚未尚未的机制，并利用受损的PM有效违反 下午障碍。这些观察结果揭示了一个新颖且显然是对比的伯氏奖和相反的方面 Anaplasma-Tick相互作用。在最近的努力中（Narasimhan等，NatCommun。184：S41467， 2017年），我们将注意力与tick肠道防御的动态互动引起人们的注意 响应以及tick虫可能影响病原体生存的各种方式 肠。这些发现以及项目1和2的观察强调了 tick肠菌菌群与病原体生存中的免疫复杂之间的相互作用。 在AIM 1中，我们将表征肠道微生物群与tick肠免疫相互作用的程度 响应（特别是JAK/STAT和IMD）和宿主细胞因子（特别是IFN），输入tick肠， 并定义受tick和宿主免疫反应显着影响的肠道细菌。 反之亦然。 在AIM 2中，我们将重建特定的肠道菌群或细菌成分，并确定如何 这影响了tick肠道免疫信号，并最终影响了B. burgdorferi或A的生存。 tick中的吞噬细胞 这项研究努力将展开对功能后果的机械理解 tick肠道菌群在tick肠免疫信号传导和两种重要的tick传播病原体的生存 这会导致人类疾病。