Targeting iron acquisition in Salmonella with siderophore-based immunization

描述（由申请人提供）：铁是宿主内细菌复制的必需元素。在细菌感染期间，最重要的宿主策略之一是通过采用高亲和力铁结合蛋白如转铁蛋白和乳铁蛋白来从微生物中螯合铁。为了克服这些宿主防御，细菌释放称为铁载体的小分子，这些小分子与铁配位，然后被细菌表达的专用摄取系统内化。宿主的对策是分泌蛋白脂质运载蛋白-2，其与铁载体的选择性基团结合，并且有效地减少细菌生长。脂质运载蛋白-2控制大肠杆菌引起的菌血症，因为它螯合铁载体肠螯合素，从而饿死大肠杆菌。铁的大肠杆菌。然而，这一战略是 针对肠道沙门氏菌血清型鼠伤寒沙门氏菌没有成功，因为该病原体除了肠螯素之外，还产生不被脂质运载蛋白-2螯合的葡糖基化肠螯素（salmochelin）。由于大量的证据表明铁的获取对于病原体在宿主中的生长是必要的，限制细菌定植的一种有希望的治疗策略是防止这些微生物获得铁。本申请的主要目的是开发新的方法来限制S.通过使用基于铁载体的免疫在脊椎动物宿主中的鼠伤寒。我们的中心假设是螯合铁载体肠杆菌素和沙门氏菌螯铁蛋白将限制S.鼠伤寒沙门氏菌，从而抑制在脊椎动物宿主中的定殖。这一假说是基于初步的数据显示，铁的收购促进S。鼠伤寒杆菌生长和与其他微生物的竞争，以及用CTB-Ent缀合物接种小鼠导致抗体产生。我们的长期目标是开发新的治疗方法，以减少S。鼠伤寒我们计划通过追求以下具体目的来检验我们的假设并实现本申请的目的：（I）本发明的第一个目的是确定注射蛋白质-铁载体缀合物是否导致S.结肠炎小鼠模型中的鼠伤寒沙门氏菌，其模拟炎性结肠炎疾病。(II)本研究的第二个目的是确定注射蛋白质-铁载体结合物是否导致S.伤寒小鼠模型中的鼠伤寒，模拟全身感染。

DESCRIPTION (provided by applicant): Iron is an essential element for the replication of bacteria inside the host. One of the most important host strategies during bacterial infections is to sequester iron from microorganisms by employing high-affinity iron-binding proteins like transferrin and lactoferrin. To overcome these host defenses, bacteria release small molecules named siderophores, which coordinate iron and are then internalized by dedicated uptake systems expressed by bacteria. A countermeasure of the host is the secretion of the protein lipocalin-2, which binds to a selective group of siderophores and it is effective in reducing bacterial growth. Lipocalin-2 controls bacteremia caused by Escherichia coli, because it chelates the siderophore enterochelin, thereby starving E. coli of iron. This strategy, however, is not successful against Salmonella enterica serotype Typhimurium because this pathogen, in addition to enterochelin, produces a glucosylated enterochelin (salmochelin) which is not sequestered by lipocalin-2. Because of the substantial evidence for the necessity of iron acquisition for the growth of pathogens in the host, one promising therapeutic strategy to limit bacterial colonization is to prevent iron acquisition by these microbes. The primary objective of this application is to develop new methods to limit iron acquisition by S. Typhimurium in the vertebrate host by using siderophore-based immunization. Our central hypothesis is that sequestering the siderophores enterobactin and salmochelin will limit iron uptake by S. Typhimurium and thereby inhibit colonization in the vertebrate host. This hypothesis is based on preliminary data revealing that iron acquisition promotes S. Typhimurium growth and competition with other microbes, and that vaccination of mice with CTB-Ent conjugates results in antibody production. Our long-range goal is to develop new treatments to reduce the growth and dissemination of S. Typhimurium. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following Specific Aims: (I) The first objective of this initiativ is to determine whether injection of protein- siderophore conjugates results in growth inhibition of S. Typhimurium in the colitis mouse model, which models inflammatory diarrheal disease. (II) The second aim of this investigation is to determine whether injection of protein-siderophore conjugates results in growth inhibition of S. Typhimurium in the typhoid mouse model, which mimics systemic infection.