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

项目3 -摘要 该建议将确定蜱肠道微生物群对蜱肠道免疫的影响 信号通路JAK/STAT和IMD及其对伯氏疏螺旋体的功能影响， 和嗜吞噬细胞无形体在蜱中的存活-感染的重要决定因素 普遍性。我们的早期工作（Narasimhan等人，Cell Host Microbe 15：58-71，2014）和我们的近期工作 （Abraham等人，Proc Natl Acad Sci，114：E781-790，2017）证明蜱肠道微生物群调节 B。burgdorferi定殖和A.肩胛硬蜱的嗜吞噬细胞菌感染。肠道扰动 微生物群（生态失调）破坏围食基质的完整性-一个富含糖蛋白的非细胞层 将肠上皮和肠腔分开。而B. Burgdorferi驻留在肠上皮上， 完整的围食基质（PM）提供了对蜱肠道中有毒成分的保护， 肠道定殖，A.嗜吞噬细胞菌绕过PM屏障感染肠道， 唾液腺通过尚未未知的机制，并利用一个妥协的PM，以有效地突破 PM屏障。这些观察揭示了疏螺旋体的一个新的和明显对比的方面-蜱， 无形体-蜱虫相互作用。在最近的努力中（Narasimhan等人，Nat Commun. 184：s41467， 2017年），我们提请注意蜱微生物群与蜱肠道防御的动态相互作用 反应和蜱虫微生物群可能影响蜱虫中病原体存活的多种方式 直觉这些结果，以及项目1和2的观察结果，强调了 蜱肠道微生物群和免疫反应之间的相互作用对蜱中病原体存活的影响。 在目标1中，我们将描述肠道微生物群与蜱肠道免疫相互作用的程度。 应答（特别是JAK/STAT和IMD）和进入蜱肠道的宿主细胞因子（特别是IFN γ）， 并确定肠道细菌谱，这些细菌谱受到蜱虫和宿主免疫反应的显著影响， 反之亦然 在目标2中，我们将重建特定的肠道微生物群或细菌成分，并确定如何 这影响蜱肠道免疫信号传导并最终影响B的存活。burgdorferi或A. 蜱中嗜吞噬细胞菌 这项研究奋进将揭示一个机械的理解的功能后果， 蜱肠道微生物群对蜱肠道免疫信号和两种重要蜱传病原体存活的影响 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.