Siderophore-based immunization strategy to inhibit growth of enteric pathogens.
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 microbiota 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 siderophore-targeted approaches may represent a novel strategy to prevent and ameliorate a broad range of infections.
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697.|Institute for Immunology, University of California, Irvine, CA 92697.
Martina
M
Sassone-Corsi
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
Phoom
P
Chairatana
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
Tengfei
T
Zheng
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697.|Institute for Immunology, University of California, Irvine, CA 92697.
Araceli
A
Perez-Lopez
Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697.
Robert A
RA
Edwards
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616.
Michael D
MD
George
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; lnolan@mit.edu manuelar@uci.edu.
Elizabeth M
EM
Nolan
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697; lnolan@mit.edu manuelar@uci.edu.|Institute for Immunology, University of California, Irvine, CA 92697.
Manuela
M
Raffatellu
D000818:Animals; D000917:Antibody Formation; D015169:Colony Count, Microbial; D004755:Enterobacteriaceae / Q000254:growth & development* / Q000276:immunology*; D005260:Female; D000069196:Gastrointestinal Microbiome; D018928:Immunity, Mucosal / Q000276:immunology; D007114:Immunization; D007249:Inflammation / Q000473:pathology; D008810:Mice, Inbred C57BL; D017262:Siderophores / Q000737:chemistry / Q000276:immunology*
D017262:Siderophores
Salmonella; immunization; iron; microbiota; siderophore