The Tick Immune Response During Microbial Infection

微生物感染期间的蜱免疫反应

• 批准号: 10414128
• 负责人: Joao Pedra
• 金额: $ 64.89万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414128
• 关键词: Address; Affect; Anaplasma phagocytophilum; Anaplasmosis; Applications Grants; Arachnida; Area; Arthropod Vectors; Arthropods; Babesia microti; Babesiosis; Basic Science; Biochemical; Bioenergetics; Bioinformatics; Biology; Black-legged Tick; Borrelia burgdorferi; Borrelia miyamotoi; Cell Wall; Cells; Cholesterol; Communicable Diseases; Communities; Coupling; Ensure; Enzymes; Europe; FADD protein; Funding; Genes; Genome; Gram-Negative Bacteria; Health; Hemocytes; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunobiology; Immunology; Infection; Infectious Disease Immunology; Insecta; Ixodes; Knowledge; Laboratories; Lead; Life; Life Cycle Stages; Life Style; Ligands; Lipids; Lipopolysaccharides; Longevity; Lyme Disease; Lysine; Mammals; Metabolic; Metabolism; Microbe; Molecular; Monoclonal Antibodies; Nuclear; Order Spirochaetales; Organism; Pathway interactions; Pattern; Peer Review; Peptidoglycan; Phylogeny; Physiology; Population; Powassan virus; Process; Proteins; Public Health; Publications; Resources; Rickettsia; Role; Signal Pathway; Signal Transduction; Textbooks; Tick-Borne Diseases; Tick-Borne Encephalitis; Tick-Borne Relapsing Fever; Ticks; Tumor Necrosis Factor Receptor; United States; Vector-transmitted infectious disease; arthropod-borne; cost effective; fitness; flexibility; granulocyte; hematophagy; infancy; interest; member; microbial; microbial colonization; novel; pathogen; peptidoglycan recognition protein; receptor; scaffold; screening; single-cell RNA sequencing; ubiquitin-protein ligase; vector; vector tick; x-linked inhibitor of apoptosis protein

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.

扁虱会传播几种与公共卫生有关的病原体， 包括伯氏疏螺旋体(莱姆病)、无浆体吞噬细胞性(人粒细胞 巴贝斯虫病(巴贝斯虫病)和波瓦桑病毒 (壁虱传播脑炎)。到目前为止，虽然已经对昆虫的不同免疫领域进行了研究，但 壁虱免疫系统的基础是它的婴儿期，以及参与微生物感应的分子 主要仍未定义。类似地，扁虱免疫细胞或血细胞的分子特征仍然存在 大部分是难以捉摸的。在之前的资助期间，我们发现了一种非典型免疫缺陷(IMD)。 结果表明，IMD途径对伯氏杆菌和A. 吞噬细胞性感染。具体地说，我们发现了作用于肩周肌IMD的分子的作用。 途径，并为扁虱的免疫系统从根本上 与昆虫不同。我们在实现三个具体目标方面取得了实质性进展，这导致 几份同行评议的出版物。对于这个R01项目(竞争续订)，我们将在之前的基础上 并研究新陈代谢和免疫学之间的关系。我们的中心假设是 新陈代谢状态的变化会影响免疫系统和扁虱的微生物感染。因此，在目标1中 在这项提议中，我们将描述在TICK中IMD通路的信号灵活性。古典课本 免疫途径的定义由一组固定的蛋白质组成，这些蛋白质放大来自 效应器的受体。我们将揭示TICK IMD途径是可塑性的，并在 代谢变化和/或微生物感染。在此拨款申请的目标2中，我们将对勾号进行分类 通过一个平台在不同的代谢和微生物条件下的血细胞种群 单细胞RNA测序(scRNA-seq)与单抗筛选策略的结合。这 病媒生物界的主要资源将表明新陈代谢和微生物感染影响扁虱 血细胞生物学。在提交的目标3中，我们将评估新陈代谢是否会影响健康参数。 与肩胛虫的生活史有关。我们还将评估跨椎骨和跨代通道 扁虱体内微生物的数量。总之，这个R01项目将证明生物能量过程可能定义了成本效益 和/或能量昂贵的扁虱-微生物相互作用。