Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 47, Pages 13462-13467Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1606290113
Keywords
siderophore; immunization; iron; Salmonella; microbiota
Categories
Funding
- Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Disease [Public Health Service (PHS)] [U54AI065359]
- PHS [AI101784, AI114625, AI105374, AI126277, AI121928, DK058057]
- Kinship Foundation Searle Scholar Award
- Massachusetts Institute of Technology (MIT) Department of Chemistry
- Burroughs Wellcome Fund
- University of California Institute for Mexico and the United States (MEXUS)
- El Consejo Nacional de Ciencia y Tecnologia (CONACYT) (MEXUS-CONACYT) award
- Royal Thai Government Fellowship
- National Science Foundation [CHE-9808061, DBI-9729592]
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Infections with Gram-negative pathogens pose a serious threat to public health. This scenario is exacerbated by increases in antibiotic resistance and the limited availability of vaccines and therapeutic tools to combat these infections. Here, we report an immunization approach that targets siderophores, which are small molecules exported by enteric Gram-negative pathogens to acquire iron, an essential nutrient, in the host. Because siderophores are nonimmunogenic, we designed and synthesized conjugates of a native siderophore and the immunogenic carrier protein cholera toxin subunit B (CTB). Mice immunized with the CTB-siderophore conjugate developed anti-siderophore antibodies in the gut mucosa, and when mice were infected with the enteric pathogen Salmonella, they exhibited reduced intestinal colonization and reduced systemic dissemination of the pathogen. Moreover, analysis of the gut micro-biota revealed that reduction of Salmonella colonization in the inflamed gut was accompanied by expansion of Lactobacillus spp., which are beneficial commensal organisms that thrive in similar locales as Enterobacteriaceae. Collectively, our results demonstrate that anti-siderophore antibodies inhibit Salmonella colonization. Because siderophore-mediated iron acquisition is a virulence trait shared by many bacterial and fungal pathogens, blocking microbial iron acquisition by siderophore-based immunization or other side-rophore-targeted approaches may represent a novel strategy to prevent and ameliorate a broad range of infections.
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