Cross-Species Immunity Signals Impacting Persistence of Tick-Borne Pathogens

跨物种免疫信号影响蜱传病原体的持久性

基本信息

批准号：
10222517
负责人：
UTPAL PAL
金额：
$ 38.63万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
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/10222517
关键词：
Address Affect Anaplasma phagocytophilum Anaplasmosis Anti-Bacterial Agents Arthropods Bacterial Infections Black-legged Tick Blood Borrelia burgdorferi Cues Culicidae Cytokine Signaling Disease Vectors Event Gatekeeping Generations Genome Goals Guanosine Triphosphate Phosphohydrolases Immune Immune response Immune signaling Immune system Immunity Immunologics Infection Ingestion Interferon Type II Interferons Invaded Investigation Ixodes Knowledge Ligands Link Modeling Molecular Order Spirochaetales Pathway interactions Production Program Research Project Grants Proteins Receptor Signaling Regulation Role STAT protein Series Signal Pathway Signal Transduction System Ticks Up-Regulation antimicrobial co-infection cytokine experimental study gut microbiome gut microbiota immunoregulation innate immune pathways insight microbicide microbiota novel operation pathogen receptor response synergism tick-borne pathogen vector vector tick

项目摘要

PROJECT 1 Abstract Despite increasing recognition of tick as a highly efficient disease vector, our knowledge of its immune system, especially how the vector recognizes and mounts antimicrobial responses to invading pathogens has been very limited. Recently, we discovered a novel cross-species signaling cascade that allows Ixodes scapularis tick to sense a specific mammalian factor present in the infected blood meal as an infection cue, triggering a potent microbicidal response that limits the proliferation of invading pathogens like Borrelia burgdorferi. These studies also uncovered a critical role of a tick “immune” GTPase, the Ixodes GTPase (IGTPase) in the tick gut, that is induced by ingested mammalian IFNγ. The IFNγ, through downstream Ixodes STAT signaling events, activates IGTPase to generate potent borreliocidal responses. In the current Project 1 of our Program Project Grant (PPG), we propose to investigate the molecular details of how this interferon-like defense operates in ticks. In our first series of experiments, we will systematically define how IFNγ induces the tick JAK/STAT pathway, including its regulation of IGTPase. We will investigate how IGTPase-induced tick antimicrobial proteins limit B. burgdorferi persistence in the vector. Besides, recent studies showed that arthropod immunity is influenced by crosstalk between discrete signaling pathways, which may impact the persistence of pathogens with overlapping range, such as B. burgdorferi and A. phagocytophilum. Therefore, our second group of experiments will examine how IFNγ-like tick defense system impacts the persistence of additional pathogens like Anaplasma phagocytophilum. We will also define the crosstalk between immune pathways, which will synergize the studies proposed in other projects of our PPG - Project 2 for defining mechanistic operation of the immune deficiency pathway (IMD) with other tick immune pathways, and the gut microbiota which is the focus of Project 3. These mechanisms altogether ultimately govern the persistence of B. burgdorferi and A. phagocytophilum. Overall, our study will shed new insight into the operation of cross- species signaling mechanisms involving discrete or co-operative tick innate immune pathway(s) that influence persistence of multiple tick-borne pathogens, including co-infection in ticks.

项目1 抽象的尽管人们越来越认识到蜱是一种高效的疾病媒介，但我们对其免疫系统的了解，尤其是载体如何识别入侵病原体并对其产生抗菌反应最近，我们发现了一种新的跨物种信号级联，可以使肩突硬蜱发挥作用。蜱虫感知受感染血粉中存在的特定哺乳动物因子作为感染线索，从而触发有效的杀菌反应，限制伯氏疏螺旋体等入侵病原体的增殖。研究还发现了蜱“免疫”GTP酶的关键作用，即蜱肠道中的Ixodes GTP酶（IGTP酶），这是由摄入的哺乳动物 IFNγ 通过下游 Ixodes STAT 信号传导事件诱导的。在我们当前的项目 1 中，激活 IGTPase 产生有效的杀疏螺旋体反应。 Grant (PPG)，我们建议研究这种干扰素样防御如何在细胞中发挥作用的分子细节。在我们的第一个系列实验中，我们将系统地定义 IFNγ 如何诱导蜱 JAK/STAT。途径，包括其对 IGTPase 的调节，我们将研究 IGTPase 如何诱导蜱抗菌。此外，最近的研究表明节肢动物具有免疫力。受到离散信号通路之间串扰的影响，这可能会影响具有重叠范围的病原体，例如伯氏疏螺旋体和嗜吞噬细胞球菌，因此，我们的第二个。一组实验将研究 IFNγ 样蜱防御系统如何影响额外的持久性我们还将定义免疫途径之间的串扰，这将与我们 PPG 的其他项目中提出的研究相结合 - 项目 2 定义机制免疫缺陷途径（IMD）与其他蜱免疫途径以及肠道微生物群的运作这是项目 3 的重点。这些机制最终共同控制 B 的持久性。总体而言，我们的研究将为交叉作用的运作提供新的见解。物种信号传导机制涉及离散或合作的蜱先天免疫途径，影响多种蜱传病原体的持续存在，包括蜱的共同感染。