Development of siderophore-based vaccines against non-typhoidal Salmonella infection

 描述(申请人提供)：非伤寒沙门氏菌是炎症性腹泻的主要原因，估计每年在美国造成140万例病例。绝大多数患者会患上胃肠炎，这是一种以炎症性腹泻为特征的自限性肠道感染。虽然肠道炎症是保护性的，因为它防止了沙门氏菌在健康人中的传播和菌血症，但炎症也通过几种机制促进沙门氏菌在肠道中的复制。与这项提议相关的是沙门氏菌在发炎的肠道中竞争必要的金属营养铁的机制。由于宿主体内的“游离”铁水平较低，沙门氏菌生物合成并输出被称为“铁载体”的小的铁清除分子，其中包括肠球蛋白和沙莫胆素。在沙门氏菌感染期间，哺乳动物宿主会分泌抗微生物蛋白Lipocalin-2。这种蛋白质与铁载体肠球蛋白结合，从而阻止微生物利用肠球蛋白作为铁源。沙门氏菌能够克服依赖于Lipocalin-2的铁饥饿，并在发炎的肠道中茁壮成长。这些铁载体是C-葡萄糖化形式的肠球蛋白，太大而不能进入Lipocalin-2的肠球蛋白结合口袋。值得注意的是，还没有确定阻止沙门氏菌介导的铁摄取的宿主防御机制。这项应用的主要目标是开发新的疫苗接种策略，以限制非伤寒沙门氏菌在肠道中对铁的获取。为此，我们建议开发针对肠球蛋白/沙莫胆素的粘膜疫苗，以抑制非伤寒沙门氏菌获取铁并减少其生长。我们还将研究肠球蛋白/沙莫胆素免疫对沙门氏菌感染的全球免疫反应和肠道微生物区系的影响。最后，我们将确定在感染沙门氏菌时，注射阻断肠球蛋白/沙莫胆素介导的铁获取的抗体是否具有保护和/或治疗效果。

 DESCRIPTION (provided by applicant): Non-typhoidal Salmonella are major causes of inflammatory diarrhea, causing an estimated 1.4 million cases per year in the United States. The vast majority of patients develop gastroenteritis, a self-limiting intestinal infection characterized by inflammatory diarrhea. Though intestinal inflammation is protective as it prevents Salmonella dissemination and bacteremia in healthy individuals, inflammation also enhances Salmonella replication in the gut via several mechanisms. Relevant to this proposal are the mechanisms by which Salmonella compete for the essential metal nutrient iron in the inflamed gut. As levels of "free" iron in the host are low, Salmonella biosynthesize and export small iron-scavenging molecules termed "siderophores" that include enterochelin and salmochelins. During Salmonella infection, the mammalian host secretes the antimicrobial protein lipocalin-2. This protein binds to the siderophore enterochelin and thereby prevents microbes from utilizing enterochelin as an iron source. Salmochelins enable Salmonella to overcome lipocalin-2-dependent iron starvation and thrive in the inflamed gut. These siderophores are C-glucosylated forms of enterochelin that are too large to fit into the enterochelin-binding pocket of lipocalin- 2. Notably, a host-defense mechanism for blocking salmochelin-mediated iron uptake by Salmonella has not been identified. The primary objective of this application is to develop new vaccination strategies to limit iron acquisition by non-typhoidal Salmonella in the intestine. To this end, we propose to develop mucosal vaccines against enterochelin/salmochelin to inhibit iron acquisition by and reduce the growth of non- typhoidal Salmonella. We will also investigate the impact of enterochelin/salmochelin immunization on the global immune response to Salmonella infection and on the intestinal microbiota. Finally, we will ascertain whether administration of antibodies blocking enterochelin/salmochelin-mediated iron acquisition has a protective and/or a therapeutic effect upon infection with Salmonella.