TY - JOUR
T1 - A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants
AU - Diard, Médéric
AU - Bakkeren, Erik
AU - Lentsch, Verena
AU - Rocker, Andrea
AU - Bekele, Nahimi Amare
AU - Hoces, Daniel
AU - Aslani, Selma
AU - Arnoldini, Markus
AU - Böhi, Flurina
AU - Schumann-Moor, Kathrin
AU - Adamcik, Jozef
AU - Piccoli, Luca
AU - Lanzavecchia, Antonio
AU - Stadtmueller, Beth M.
AU - Donohue, Nicholas
AU - van der Woude, Marjan W.
AU - Hockenberry, Alyson
AU - Viollier, Patrick H.
AU - Falquet, Laurent
AU - Wüthrich, Daniel
AU - Bonfiglio, Ferdinando
AU - Loverdo, Claude
AU - Egli, Adrian
AU - Zandomeneghi, Giorgia
AU - Mezzenga, Raffaele
AU - Holst, Otto
AU - Meier, Beat H.
AU - Hardt, Wolf Dietrich
AU - Slack, Emma
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7
Y1 - 2021/7
N2 - 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 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 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 variation4,5. 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.
AB - 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 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 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 variation4,5. 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.
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U2 - 10.1038/s41564-021-00911-1
DO - 10.1038/s41564-021-00911-1
M3 - Article
C2 - 34045711
AN - SCOPUS:85106708581
SN - 2058-5276
VL - 6
SP - 830
EP - 841
JO - Nature Microbiology
JF - Nature Microbiology
IS - 7
ER -