Functional Microbiomics, Inflammation and Pathogenicity

摘要 炎症对于保护我们免受感染是必不可少的。为了控制感染，白细胞必须迅速感觉到 病原体并招募额外的免疫细胞到受感染的组织。然而，一旦感染得到控制， 炎症也必须迅速消除，以避免由激活的免疫细胞造成的侧枝组织损害。 因此，炎症的启动和消退是严格调控的过程。血管紧张素转换酶的脂质介体 炎症对炎症的启动和消退都是必不可少的。白三烯B4(LTB4)是一种前白三烯B4。 感染后迅速产生的炎性脂质。与BLT1受体结合的LTB4和 激活驻留和循环中的白细胞到感染部位，需要LTB4/BLT1信号来 有效控制感染。然而，持续的LTB4合成也会导致慢性炎症和 与炎症性疾病相关的组织损伤，如痛风、哮喘和矽肺。因为 LTB4的失调影响急性和慢性炎症，定义了这一特定的贡献 有效的化学诱导剂对炎症的调节是理解其分子机制的关键。 炎症的启动和消退。我们已经证明了LTB4介导的调节失调 炎症发生在二氧化硅引起的无菌炎症(即持续的LTB4产生)和耶尔森氏菌 鼠疫菌感染(即抑制LTB4的产生)。虽然我们已经确定了这个信号通路在 这两种疾病，这种失调的确切性质及其对炎性细胞编程的影响仍然存在 我们在LTB4调节炎症反应方面的知识存在严重差距。因此，目标是 该项目将使用路易斯维尔大学科布尔斯和肯塔基州的核心资源中心 INBRE研究二氧化硅诱导的LTB4失调时炎症的时空调节 吸入或鼠疫杆菌感染。我们将通过应用尖端技术来实现这一目标 包括单细胞RNA测序和成像质量细胞术。对这些监管机制的定义是 了解炎症如何得到适当控制并揭示潜在治疗干预措施的关键 更好地治疗慢性炎症引起的感染和疾病。

ABSTRACT Inflammation is essential to protect us against infection. To contain the infection, leukocytes must rapidly sense pathogens and recruit additional immune cells to infected tissues. However, once the infection is contained, inflammation must also be quickly resolved to avoid collateral tissue damage caused by activated immune cells. Therefore, initiation and resolution of inflammation are tightly regulated processes. Lipid mediators of inflammation are essential for both the initiation and resolution of inflammation. Leukotriene B4 (LTB4) is a pro- inflammatory lipid rapidly produced in response to infection. LTB4 binding to the BLT1 receptor recruits and activates resident and circulating leukocytes to sites of infection, and LTB4/BLT1 signaling is required to effectively control infections. However, persistent LTB4 synthesis can also lead to chronic inflammation and tissue damage associated with inflammatory diseases such as gout, asthma, and silicosis. Because dysregulation of LTB4 impacts both acute and chronic inflammation, defining the specific contribution of this potent chemoattractant to the regulation of inflammation is essential to understanding the molecular mechanisms of inflammatory initiation and resolution. We have demonstrated that dysregulation of LTB4-mediated inflammation occurs during both silica-induced sterile inflammation (i.e., persistent LTB4 production) and Yersinia pestis infection (i.e., inhibited LTB4 production). While we have established a role for this signaling pathway in both diseases, the precise nature of this dysregulation and its impact on inflammatory cell programming remains a critical gap in our knowledge pertaining to LTB4 regulation of inflammatory responses. Therefore, the goal of this project is to use the Core Resource Centers at the University of Louisville's COBREs and the Kentucky INBRE to define the temporal and spatial regulation of inflammation during LTB4 dysregulation induced by silica inhalation or Y. pestis infection. We will achieve this through the application of cutting-edge technologies including single cell RNA sequencing and imaging mass cytometry. Defining these mechanisms of regulation is key to understanding how inflammation is properly controlled and can reveal potential therapeutic interventions to better treat infection and diseases resulting from chronic inflammation.