A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants

Diard, Médéric and Bakkeren, Erik and Lentsch, Verena and Rocker, Andrea and Bekele, Nahimi Amare and Hoces, Daniel and Aslani, Selma and Arnoldini, Markus and Böhi, Flurina and Schumann-Moor, Kathrin and Adamcik, Jozef and Piccoli, Luca and Lanzavecchia, Antonio and Stadtmueller, Beth M. and Donohue, Nicholas and van der Woude, Marjan W. and Hockenberry, Alyson and Viollier, Patrick H. and Falquet, Laurent and Wüthrich, Daniel and Bonfiglio, Ferdinando and Loverdo, Claude and Egli, Adrian and Zandomeneghi, Giorgia and Mezzenga, Raffaele and Holst, Otto and Meier, Beat H. and Hardt, Wolf-Dietrich and Slack, Emma. (2021) A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants. Nature Microbiology, 6 (7). pp. 830-841.

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The ability of gut bacterial pathogens to escape immunity by antigenic variation-particularly via changes to surface-exposed antigens-is a major barrier to immune clearance; 1; . However, not all variants are equally fit in all environments; 2,3; . It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate 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 variation; 4,5; . We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB. Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Pathogen Evolution (Diard)
UniBasel Contributors:Diard, Médéric
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Dec 2021 11:19
Deposited On:01 Dec 2021 11:19

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