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

 描述（由申请人提供）：非伤寒沙门氏菌是炎症性腹泻的主要原因，在美国每年估计造成140万例病例。绝大多数患者发展为胃肠炎，一种以炎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，因为它可以防止健康个体中的沙门氏菌传播和菌血症，但炎症也可以通过几种机制增强沙门氏菌在肠道中的复制。与此相关的是沙门氏菌在发炎肠道中竞争必需金属营养铁的机制。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称为“铁载体”的小铁清除分子，包括肠螯合素和沙门氏菌螯合素。在沙门氏菌感染期间，哺乳动物宿主分泌抗微生物蛋白脂质运载蛋白-2。这种蛋白质结合铁载体肠螯合素，从而防止微生物利用肠螯合素作为铁源。Salmochelins使沙门氏菌能够克服脂质运载蛋白-2依赖的铁饥饿，并在发炎的肠道中茁壮成长。这些铁载体是肠螯合素的C-葡萄糖基化形式，其太大而不能装入脂质运载蛋白-2的肠螯合素结合口袋中。值得注意的是，尚未鉴定出沙门氏菌阻断沙门氏菌螯铁蛋白介导的铁摄取的宿主防御机制。本申请的主要目的是开发新的疫苗接种策略，以限制肠道中非伤寒沙门氏菌的铁获取。为此，我们建议开发针对肠螯素/螯鲑素的粘膜疫苗，以抑制非伤寒沙门氏菌的铁获取并减少其生长。我们还将研究肠螯素/沙门氏菌螯素免疫对沙门氏菌感染的全球免疫应答和肠道微生物群的影响。最后，我们将确定阻断肠螯素/salmochelin介导的铁获取的抗体的施用是否对沙门氏菌感染具有保护和/或治疗作用。

 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.