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: 9976334
• 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/9976334
• 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 尽管人们越来越多地认识到扁虱是一种高效的疾病媒介，但我们对其免疫系统的了解， 尤其是媒介如何识别和安装对入侵病原体的抗菌素反应 非常有限。最近，我们发现了一种新的跨物种信号级联，它允许肩部硬蜱 勾选以感知感染血餐中存在的特定哺乳动物因子作为感染提示，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。这些 研究还发现了硬蜱GTP酶(IGTPase)的一个关键作用，该酶是壁虱肠道中的一种“免疫”GTP酶。 这是由摄取的哺乳动物干扰素γ诱导的。干扰素γ，通过下游的硬蜱STAT信号事件， 激活IGTP酶以产生有效的杀螺旋体反应。在我们计划项目的当前项目1中 Grant(PPG)，我们建议研究这种干扰素样防御如何在 滴答滴答。在我们的第一系列实验中，我们将系统地定义干扰素γ是如何诱导tick JAK/STAT的 途径，包括其对IGTPase的调节。我们将研究IGTPase是如何诱导壁虱抗菌的 蛋白质限制了伯氏杆菌在载体中的持久性。此外，最近的研究表明，节肢动物的免疫力 受到离散信号通路之间的串扰的影响，这可能会影响 范围重叠的病原体，如伯氏杆菌和吞噬细胞性芽孢杆菌。因此，我们的第二个 一组实验将研究干扰素γ样扁虱防御系统如何影响额外的 病原体，如吞噬细胞性无浆体。我们还将定义免疫通路之间的串扰， 它将协同我们的PPG-项目2的其他项目中提出的研究，以定义机械 免疫缺陷途径(IMD)与其他扁虱免疫途径的运作，以及肠道微生物区系 这是项目3的重点。这些机制最终决定了B的持久性。 Burgdorferi和吞噬细胞性弧菌。总体而言，我们的研究将为交叉投资的运作提供新的见解。 物种信号传递机制，涉及离散或合作的壁虱先天免疫途径(S)，影响 持续存在多种硬体传播的病原体，包括硬体内的混合感染。