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

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 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.