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

项目3-摘要 这项建议将决定硬体动物肠道微生物区系对硬体动物肠道免疫的影响。 信号通路JAK/STAT和IMD及其对伯氏疏螺旋体的功能影响 扁虱体内的吞噬细胞无形体存活--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)证明扁虱肠道微生物区系调节 伯氏嗜血杆菌定植与肩部硬蜱的吞噬细胞性感染。肠扰动 微生物区系(生物失调)破坏了营养周围基质的完整性--一种富含非细胞糖蛋白的层 这将肠道上皮与肠腔分开。而伯氏杆菌则栖息在肠道上皮细胞和 完整的围食基质(PM)提供保护，使其免受壁虱肠道中有毒成分的伤害，从而增强其 肠道的定植，吞噬细胞性弧菌绕过PM屏障感染肠道，最终感染 唾液腺通过尚不清楚的机制，并利用受攻击的PM有效地破坏 PM屏障。这些观察揭示了疏螺旋体的一个新的和明显相反的方面 无浆体-壁虱相互作用。在最近的一项努力中(Narasimhan等人，NAT Commun。184：S41467， 2017)中，我们提请注意壁虱微生物区系与壁虱肠道防御的动态相互作用 对硬蜱微生物区系影响病原体存活的不同方式的反应 直觉。这些调查结果与项目1和2的观察结果一起强调了 硬蜱肠道微生物区系与病原体存活的免疫反应之间的相互作用。 在目标1中，我们将描述肠道微生物区系与壁虱肠道免疫相互作用的程度。 进入扁虱肠道的应答(特别是JAK/STAT和IMD)和宿主细胞因子(特别是干扰素)， 并确定受扁虱和宿主免疫反应显著影响的肠道细菌图谱 反之亦然。 在目标2中，我们将重建特定的肠道微生物区系或细菌成分，并确定如何 这会影响壁虱肠道免疫信号，最终影响伯氏杆菌或A. 扁虱体内的吞噬细胞 这项研究的努力将展开对功能后果的机械性理解 壁虱肠道微生物区系对壁虱肠道免疫信号和两种重要壁虱传播病原体生存的影响 会导致人类疾病。

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.