A rationally designed oral vaccine induces Immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants
| Autor: | Daniel Hoces, Verena Lentsch, Selma Aslani, Nicholas Donohue, Claude Loverdo, Wolf-Dietrich Hardt, Patrick H. Viollier, Laurent Falquet, Otto Holst, Marjan W. van der Woude, Emma Slack, Erik Bakkeren, Markus Arnoldini, Jozef Adamcik, Nahimi Amare Bekele, Ferdinando Bonfiglio, Giorgia Zandomeneghi, Luca Piccoli, Raffaele Mezzenga, Beth M. Stadtmueller, Andrea Rocker, Médéric Diard, Adrian Egli, Alyson M. Hockenberry, Flurina Böhi, Kathrin Schumann-Moor, Beat H. Meier, Antonio Lanzavecchia, Daniel Wüthrich |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Salmonella biology 030306 microbiology Virulence biology.organism_classification medicine.disease_cause 3. Good health Microbiology 03 medical and health sciences Immune system Antigen Salmonella enterica Immunity biology.protein medicine Antigenic variation Antibody 030304 developmental biology |
| DOI: | 10.1101/824821 |
| Popis: | Introductory paragraphThe ability of gut bacterial pathogens to escape immunity by antigenic variation, particularly via changes to surface-exposed antigens, is a major barrier to immune clearance1. However, not all variants are equally fit in all environments2, 3. It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here we demonstrated this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm). A dominant surface antigen of S.Tm is its O-antigen: A long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase-variation4, 5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen specific IgA and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naïve mice. Through the use of oral vaccines, we rationally induced IgA responses blocking all of these trajectories, which selected for Salmonella mutants carrying deletions of the O-antigen polymerase wzyB. Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents, complement), predation (bacteriophages), and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S.Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy. |
| Databáze: | OpenAIRE |
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