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

• 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
• 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

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 摘要 尽管人们越来越认识到蜱虫是一种高效的疾病载体，但我们对其免疫系统的了解， 特别是载体如何识别并对入侵的病原体产生抗菌反应， 非常有限。最近，我们发现了一种新的跨物种信号级联， 蜱虫感知到感染的血液中存在的特定哺乳动物因子作为感染线索，从而触发 有效的杀微生物反应，限制入侵病原体如伯氏疏螺旋体的增殖。这些 研究还揭示了蜱“免疫”GTdR，蜱肠道中的硬蜱GTdR（IGTdR）， 这是由摄入的哺乳动物IFNγ诱导的。IFNγ通过下游的Ixodes STAT信号传导事件， 激活IGT β产生有效的杀疏螺旋体反应。在当前的项目1我们的计划项目 格兰特（PPG），我们建议调查这种干扰素样防御如何在细胞中运作的分子细节。 滴答声。在我们的第一系列实验中，我们将系统地定义IFNγ如何诱导蜱JAK/STAT 途径，包括其对IGT β的调节。我们将研究IGTPase-induced蜱抗菌 蛋白质限制B。burgdorferi持久性在载体中。此外，最近的研究表明，节肢动物免疫 受离散信号通路之间的串扰影响，这可能会影响 范围重叠的病原体，如B。burgdorferi和A.嗜吞噬细胞菌因此，我们的第二 一组实验将研究IFNγ样蜱防御系统如何影响额外的持续性， 病原体如嗜吞噬细胞无形体我们还将定义免疫途径之间的串扰， 这将协同我们的PPG的其他项目中提出的研究-项目2，用于定义机械 免疫缺陷途径（IMD）与其他蜱免疫途径的运作，以及肠道微生物群 这是项目3的重点。这些机制最终共同决定了B的持久性。 burgdorferi和A.嗜吞噬细胞菌总的来说，我们的研究将为跨部门的运作提供新的见解， 种属信号传导机制，涉及离散或合作蜱先天免疫途径， 多种蜱传病原体的持续存在，包括蜱中的合并感染。