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.

Public Health Relevance

Non-typhoidal Salmonella causes 1.4 million infections in the United States each year, and no vaccine is currently available to prevent this infection. Our approach is to develop innovative mucosal vaccines aiming to block siderophore-mediated iron acquisition by Salmonella in the gut and thereby reduce the colonization and the dissemination of this pathogen, by this means addressing this important public health issue.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Alexander, William A
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Neumann, Wilma; Sassone-Corsi, Martina; Raffatellu, Manuela et al. (2018) Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin-Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity. J Am Chem Soc 140:5193-5201
Neumann, Wilma; Nolan, Elizabeth M (2018) Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. J Biol Inorg Chem 23:1025-1036
Chung, Lawton K; Raffatellu, Manuela (2018) G.I. pros: Antimicrobial defense in the gastrointestinal tract. Semin Cell Dev Biol :
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Johnstone, Timothy C; Nolan, Elizabeth M (2017) Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography. J Am Chem Soc 139:15245-15250
Neumann, Wilma; Gulati, Anmol; Nolan, Elizabeth M (2017) Metal homeostasis in infectious disease: recent advances in bacterial metallophores and the human metal-withholding response. Curr Opin Chem Biol 37:10-18
Neumann, Wilma; Hadley, Rose C; Nolan, Elizabeth M (2017) Transition metals at the host-pathogen interface: how Neisseria exploit human metalloproteins for acquiring iron and zinc. Essays Biochem 61:211-223
Sassone-Corsi, Martina; Nuccio, Sean-Paul; Liu, Henry et al. (2016) Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540:280-283
Diaz-Ochoa, Vladimir E; Lam, Diana; Lee, Carlin S et al. (2016) Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration. Cell Host Microbe 19:814-25
Sassone-Corsi, Martina; Chairatana, Phoom; Zheng, Tengfei et al. (2016) Siderophore-based immunization strategy to inhibit growth of enteric pathogens. Proc Natl Acad Sci U S A 113:13462-13467

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