A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants.
A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants.
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DOI：
10.1038/s41564-021-00911-1
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发表时间：
2021-07
影响因子：
28.3
通讯作者：
Slack E
中科院分区：
文献类型：
--
作者：
Diard M;Bakkeren E;Lentsch V;Rocker A;Bekele NA;Hoces D;Aslani S;Arnoldini M;Böhi F;Schumann-Moor K;Adamcik J;Piccoli L;Lanzavecchia A;Stadtmueller BM;Donohue N;van der Woude MW;Hockenberry A;Viollier PH;Falquet L;Wüthrich D;Bonfiglio F;Loverdo C;Egli A;Zandomeneghi G;Mezzenga R;Holst O;Meier BH;Hardt WD;Slack E
肠道细菌病原体通过抗原变异（特别是通过表面暴露抗原的变化）逃避免疫的能力是免疫清除的主要障碍。然而，并非所有变体都同样适合所有环境。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，我们使用肠沙门氏菌亚种伤寒沙门氏菌（S.Tm）证明了这种现象。 S.Tm 的主要表面抗原是其 O 抗原：一种长的重复聚糖，可以通过生物合成途径中的突变或相变而快速变化。我们量化了 O 抗原变体在存在和不存在 O 抗原特异性 IgA 的情况下的选择性优势，并确定了一组允许免疫逃逸的进化轨迹，而无需在幼稚小鼠中产生相关的健康成本。通过使用口服疫苗，我们合理诱导 IgA 反应，阻断所有这些轨迹，从而选择携带 O 抗原聚合酶 wzyB 缺失的沙门氏菌突变体。由于 O 抗原较短，这些进化的突变体更容易受到环境压力（去污剂、补体）、捕食（噬菌体）的影响，并且在小鼠体内的肠道定植和毒力受到损害。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。
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. 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-variation. 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.
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影响因子：
3.7
作者：
Felmy B;Songhet P;Slack EM;Müller AJ;Kremer M;Van Maele L;Cayet D;Heikenwalder M;Sirard JC;Hardt WD
通讯作者：
Hardt WD
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
46.9
作者：
Bikard, David;Euler, Chad W.;Jiang, Wenyan;Nussenzweig, Philip M.;Goldberg, Gregory W.;Duportet, Xavier;Fischetti, Vincent A.;Marraffini, Luciano A.
通讯作者：
Marraffini, Luciano A.
影响因子：
56.9
作者：
Diard, Mederic;Bakkeren, Erik;Hardt, Wolf-Dietrich
通讯作者：
Hardt, Wolf-Dietrich
影响因子：
3.3
作者：
Cherry, Joshua L.
通讯作者：
Cherry, Joshua L.