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

项目摘要 暴露于吸血节肢动物的叮咬， 脊椎动物宿主这些反应在很大程度上归因于接种节肢动物来源的唾液 蛋白质进入皮肤。反过来，由唾液蛋白引起的免疫力显著影响免疫的结果。 感染后，随后暴露于节肢动物传播的病原体。然而，免疫学事件 以及更重要的是，这些事件在生理环境中如何变化 反复暴露的风险，并没有很好的定义。此外，如果以及如何适应性免疫应答唾液 蛋白质直接影响病原体特异性细胞的活化是未知的。如果没有一个清洁工 了解唾液和病原体特异性免疫之间的相互作用， 免疫系统预防或治疗病媒传播疾病的能力可能仍然不足。 在初步的实验中，我们发现小鼠的适应性和先天性免疫反应， 未受感染的长须沙蝇的叮咬，一种吸血节肢动物和利什曼病的媒介 由原生动物寄生病原体利什曼原虫引起，随着反复暴露于未感染的叮咬而变化。 在反复暴露于血液喂养期间，唾液蛋白特异性T辅助细胞的初始均质相 (Th)1免疫让位于群体水平的异质性应答，并改变单核细胞应答。 长期预先暴露于 未感染叮咬对利什曼特异性免疫的影响以及唾液特异性免疫的机制 利什曼病特异性免疫的影响是未知的。 根据这些观察，我们假设，在初始Th 1主导的应答之后， 血液喂养，免疫系统经历了多样化与持续的慢性暴露，导致 涉及多种CD 4 T细胞亚群的异源性应答。考虑到沙蝇和 寄生虫衍生的抗原，包括微生物群，在利什曼感染的白蛉叮咬部位的皮肤，唾液， 或细菌特异性T细胞随后将通过CCR 2+炎性细胞因子影响利什曼病特异性免疫。 单核细胞许可证。这些假设将在以下两个目标内进行实验检验：AIM 1： 确定对白蛉叮咬和白蛉衍生抗原的先天性和适应性免疫如何随着 反复暴露。目的2：确定慢性暴露于白蛉叮咬对新生 利什曼特异性T细胞的产生，并确定CCR 2+单核细胞作为中心抗原的作用 细胞在这个过程中。 进行这些研究将提供一个关键的临床前理解如何"宿主-载体- 病原体的关系可能会影响预防和治疗干预策略的成功， 节肢动物传播的疾病

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.