Defining a role for monocyte licensing in the regulation of Leishmania-specific T cell immunity following short- and long-term pre-exposure to sand fly blood feeding

确定单核细胞许可在短期和长期接触白蛉吸血后利什曼原虫特异性 T 细胞免疫调节中的作用

• 批准号: 10308416
• 负责人: Nathan C. Peters
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308416
• 关键词: Anatomy; Anti-Bacterial Agents; Antigen-Presenting Cells; Antigens; Arthropod Vectors; Arthropods; Bacteria; Biological; Bite; Blood; CD4 Antigens; CD4 Positive T Lymphocytes; Cells; Chronic; Cutaneous Leishmaniasis; Dermis; Disease; Event; Exposure to; Frequencies; Generations; Grant; Host resistance; Immune response; Immune system; Immunity; Immunologics; Infection; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interferons; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Intervention; Leishmania; Leishmaniasis; Licensing; Light; Mediating; Mus; Natural Immunity; Outcome; Parasites; Phase; Phenotype; Physiological; Population; Predisposition; Preventative vaccination; Process; Regulation; Reporting; Research; Role; Saliva; Salivary; Salivary Proteins; Sand Flies; Site; Skin; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Vector-transmitted infectious disease; adaptive immune response; adaptive immunity; arthropod-borne; commensal bacteria; experimental study; feeding; immunogenic; immunoregulation; interleukin-22; microbiota; monocyte; pathogen; pre-clinical; prevent; prophylactic; response; success; transmission process; vector; wound healing

Project Summary Exposure to the bites of blood feeding arthropods elicits both innate and adaptive immune responses in the vertebrate host. These responses have largely been attributed to inoculation of arthropod-derived salivary proteins into the skin. In turn, immunity elicited by salivary proteins significantly influences the outcome of infection upon subsequent exposure to arthropod transmitted pathogens. However, the immunological events that occur following blood feeding, and more importantly, how these events change in the physiological setting of repeated exposure, are not well defined. In addition, if and how the adaptive immune response to salivary proteins directly influences the activation of pathogen-specific cells is not known. Without a clearer understanding of the interactions between salivary- and pathogen-specific immunity our ability to harness the power of the immune system to prevent or treat vector-transmitted diseases is likely to remain inadequate. In preliminary experiments, we have found that the murine adaptive and innate immune responses to the bites of uninfected Lutzomia longipalpus sand flies, a blood feeding arthropod and vector of leishmaniasis caused by the protozoan parasitic pathogen Leishmania, changes with repeated exposure to uninfected bites. During repeated exposure to blood feeding an initial homogenous phase of salivary protein-specific T helper (Th) 1 immunity gives way to a heterogenous response at the population level and alters the monocyte response. Both the impact of the diverse and likely cross-regulatory responses elicited by long-term pre-exposure to uninfected bites on Leishmania-specific immunity and the mechanism by which salivary-specific immunity influences Leishmania-specific immunity are unknown. In light of these observations, we HYPOTHESIZE that, following an initial Th1 dominated response to blood feeding, the immune system undergoes a diversification with ongoing chronic exposure resulting in a heterogenous response involving multiple CD4 T cell subsets. Given the intimate co-localization of sand fly- and parasite-derived antigens, including the microbiota, at a Leishmania-infected sand fly bite site in the skin, saliva- or bacteria- specific T cells will subsequently impact Leishmania-specific immunity via CCR2+ inflammatory monocyte licensing. These hypotheses will be tested experimentally within the following two aims: AIM 1: Determine how innate and adaptive immunity to sand fly bites and sand fly derived antigens changes with repeated exposure.; and AIM 2: Determine the impact of chronic exposure to sand fly bites on de novo generation of Leishmania-specific T cells and define a role for CCR2+ monocytes as the central antigen presenting cell in this process. Conducting these studies will provide a critical pre-clinical understanding of how the ‘host-vector- pathogen’ relationship may impact the success of prophylactic and therapeutic intervention strategies to treat arthropod transmitted diseases.

项目摘要 暴露于血液喂养节肢动物的一部分 脊椎动物主机。这些反应在很大程度上归因于接种节肢动物衍生的唾液 蛋白质进入皮肤。反过来，唾液蛋白引起的免疫力显着影响 随后暴露于节肢动物传播病原体后的感染。但是，免疫事件 这是在血液喂养之后发生的，更重要的是，这些事件如何在物理环境中发生变化 反复暴露的定义不当。另外，如果以及如何适应性免疫反应 蛋白质直接影响病原体特异性细胞的激活尚不清楚。没有更清晰的 了解唾液和病原体特异性免疫之间的相互作用我们利用的能力 免疫系统预防或治疗载体传播疾病的功率可能保持不足。 在初步实验中，我们发现鼠适应性和先天免疫反应 未感染的lutzomia longipalpus sand蝇，血液喂养节肢动物和利什曼病的向量 由原生动物寄生虫病原体利什曼原虫引起的，反复暴露于未感染的叮咬会变化。 在反复接触血液中，唾液蛋白特异性T助手的初始同质阶段 （TH）1免疫学在人群水平上取代异源反应并改变单核细胞反应。 长期暴露于 利什曼尼亚特异性免疫的未感染位和唾液特异性免疫的机制 影响利什曼尼亚特异性免疫力是未知的。 鉴于这些观察结果，我们假设在初始TH1之后，对 血液喂养，免疫系统经历了多元化，持续的慢性暴露导致 涉及多个CD4 T细胞亚群的异质反应。鉴于沙蝇和 寄生虫衍生的抗原，包括微生物群，在皮肤中的利什曼尼亚感染的砂蝇叮咬部位，唾液 - 或细菌特异性T细胞随后会通过CCR2+炎症影响利什曼原虫特异性的免疫力 单核细胞许可。这些假设将在以下两个目标中进行实验测试：AIM 1： 确定与先天和适应性的免疫力，可随着沙子叮咬和沙蝇衍生的抗原的变化如何变化 反复接触。;和目标2：确定长期暴露于沙蝇对从头的影响 Leishmania特异性T细胞的产生，并将CCR2+单核细胞的作用定义为中央抗原 在此过程中呈现细胞。 进行这些研究将为临时临时理解提供对宿主矢量 病原体的关系可能会影响预防性和治疗干预策略的成功 节肢动物传播疾病。