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 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.

肠道细菌病原体通过抗原变异（尤其是通过改变表面暴露的抗原）逃避免疫的能力是免疫清除的主要障碍¹。但是，并非所有变体都同样适合所有环境^2,3。因此，应该有可能利用这种免疫逃逸机制来指导进化权衡。在这里，我们使用沙门氏菌肠炎亚种肠炎血清型鼠伤寒 ( S.Tm )来证明这一现象。S .Tm的主要表面抗原是其 O 抗原：一种长而重复的聚糖，可通过生物合成途径中的突变或通过相位变化^{4,5快速变化}. 我们量化了 O 抗原变体在存在和不存在 O 抗原特异性免疫球蛋白 A 的情况下的选择性优势，并确定了一组进化轨迹，允许免疫逃逸而不会在幼稚小鼠中产生相关的适应性成本。通过使用合理设计的口服疫苗，我们诱导免疫球蛋白 A 反应阻断所有这些轨迹。这选择了携带 O 抗原聚合酶基因wzyB缺失的沙门氏菌突变体. 由于它们的 O 抗原短，这些进化的突变体更容易受到环境压力（去污剂或补体）和捕食（噬菌体）的影响，并且在小鼠的肠道定植和毒力方面受损。因此，合理诱导的肠道抗体混合物可以指导 S.Tm 的进化权衡。这为探索能够设置进化陷阱作为预防策略的粘膜疫苗奠定了基础。