The Tick Immune Response During Microbial Infection

肩胛硬蜱传播与公共卫生相关的几种病原体， 包括伯氏疏螺旋体（莱姆病）、嗜吞噬细胞无形体（人粒细胞 无形体病）、B. miyamotoi（蜱传回归热）、Babeidae microti（巴贝虫病）和Powassan病毒 （蜱传脑炎）。迄今为止，虽然已经在昆虫中研究了不同的免疫领域， 蜱虫免疫系统的基础还处于起步阶段，参与微生物传感的分子 主要是不确定的。同样，蜱免疫细胞或血细胞的分子特征仍然存在， 大多是难以捉摸的在上一个资助期间，我们发现了一种非典型免疫缺陷（IMD） 网络I。并显示IMD途径对B是重要的。burgdorferi和A. 嗜吞噬细胞菌感染具体地说，我们揭示了作用于I.肩胛肌IMD 途径，并提供了一个观察机制的支持，蜱的免疫系统是从根本上 不同于昆虫。我们在实现三个具体目标方面取得了实质性进展， 一些同行评审的出版物。对于这个R 01项目（竞争性更新），我们将建立在我们早期的 研究结果，并研究代谢和免疫学之间的联系。我们的核心假设是， 代谢状态的变化会影响蜱虫的免疫系统和微生物感染。因此，目标#1 在这个提议中，我们将描述蜱中IMD途径的信号传导灵活性。古典教科书 免疫途径的定义是由一组固定的蛋白质组成，这些蛋白质放大来自免疫系统的免疫信号。 受体到效应器。我们将揭示，蜱IMD途径是可塑性的，并重新编程后， 代谢变化和/或微生物感染。在本资助申请的目标#2中，我们将对蜱虫进行分类， 血细胞群体在不同的代谢和微生物条件下通过一个平台， 单细胞RNA测序（scRNA-seq）与单克隆抗体筛选策略的偶联。这 病媒生物界的主要资源将表明，新陈代谢和微生物感染会影响蜱虫 血细胞生物学在本次提交的目标3中，我们将评估代谢是否会影响健身参数 与I的生命周期相关。肩胛肌我们还将评估跨stadial和跨代传递 微生物的数量。总而言之，这个R 01项目将证明，生物能过程可能定义成本效益 和/或能量昂贵的蜱-微生物相互作用。

The tick Ixodes scapularis transmits several pathogens of relevance to public health, including Borrelia burgdorferi (Lyme disease), Anaplasma phagocytophilum (human granulocytic anaplasmosis), B. miyamotoi (tick-borne relapsing fever), Babesia microti (babesiosis) and Powassan virus (tick-borne encephalitis). To date, while diverse areas of immunity have been studied in insects, the underpinnings of the tick immune system are in its infancy, and the molecules involved in microbial sensing remain chiefly undefined. Similarly, the molecular characterization of tick immune cells or hemocytes remains mostly elusive. Over the previous funding period, we discovered a non-canonical immune deficiency (IMD) network in I. scapularis and showed that the IMD pathway is important against B. burgdorferi and A. phagocytophilum infection. Specifically, we uncovered the role of molecules that act on the I. scapularis IMD pathway and provided mechanistic support for an observation that the immune system of ticks is fundamentally different than insects. We made substantial progress in addressing the three specific aims, which resulted in several peer-reviewed publications. For this R01 project (competing renewal), we will build on our earlier findings and investigate the nexus between metabolism and immunology. Our central hypothesis states that changes in metabolic status impact the immune system and microbial infection of ticks. Accordingly, in Aim #1 of this proposal, we will characterize the signaling flexibility of the IMD pathway in ticks. The classical textbook definition of an immune pathway consists of a fixed stack of proteins that amplifies the immune signal from a receptor to an effector. We will reveal that the tick IMD pathway is malleable and reprograms itself upon metabolic changes and/or microbial infection. In Aim #2 of this grant application, we will categorize tick hemocyte populations under distinct metabolic and microbial conditions through a platform that involves coupling of single cell RNA sequencing (scRNA-seq) with a monoclonal antibody screening strategy. This major resource to the vector biology community will show that metabolism and microbial infection affect tick hemocyte biology. In Aim #3 of this submission, we will assess whether metabolism affects fitness parameters associated with the life cycle of I. scapularis. We will also evaluate transstadial and transgenerational passage of microbes in ticks. Altogether, this R01 project will demonstrate that bioenergetic processes likely define cost-effective and/or energetically expensive tick-microbe interactions.