Journal
NATURE MICROBIOLOGY
Volume 6, Issue 7, Pages 830-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41564-021-00911-1
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Funding
- Swiss National Science Foundation professorship [PP00PP_176954]
- Gebert Ruf Microbials [PhagoVax GRS-093/20, GR073_17]
- Swiss National Science Foundation [40B2-0_180953, 310030_185128, 310030B-173338, 310030_192567, 200020_159707]
- European Research Council Consolidator Grant
- NIAID NIH HHS/United States [R01 AI041239/AI]
- ProMedica Foundation
- Gebert Ruf Foundation
- Helmut Horten Foundation
- Boehringer Ingelheim Fonds PhD fellowship
- Swiss National Science Foundation (SNF) [310030_185128, 40B2-0_180953, 310030_192567] Funding Source: Swiss National Science Foundation (SNF)
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The study demonstrates the possibility of exploiting immune escape mechanisms to direct an evolutionary trade-off in gut bacterial pathogens using Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm). By inducing O-antigen-specific immunoglobulin A responses through rational designed oral vaccines, the study successfully selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB, leading to impaired gut colonization and virulence in mice. This research lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy.
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'. 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.
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