Typhoidal and non-typhoidal Salmonelleae (NTS) cause typhoid fever and gastroenteritis, respectively, in humans. Salmonella typhoid toxin contributes to typhoid disease progression and chronic infection, but little is known about the role of its NTS ortholog. We found that typhoid toxin and its NTS ortholog induce different clinical presentations. The PltB subunit of each toxin exhibits different glycan-binding preferences that correlate with glycan expression profiles of host cells targeted by each bacterium at the primary infection or intoxication sites. Through co-crystal structures of PltB subunits bound to specific glycan receptor moieties, we show that they induce markedly different glycan-binding preferences and virulence outcomes. Furthermore, immunization with the NTS S. Javiana or its toxin offers cross-reactive protection against lethal-dose typhoid toxin challenge. Cumulatively, these results offer insights into the evolution of host adaptations in Salmonella AB toxins, their cell and tissue tropisms, and the design for improved typhoid vaccines and therapeutics.

伤寒沙门氏菌和非伤寒沙门氏菌分别导致人类伤寒和肠胃炎。伤寒沙门氏菌毒素有助于伤寒疾病的发展和慢性感染，但对其NTS直系同源物的作用了解甚少。我们发现伤寒毒素及其NTS直向同源物诱导不同的临床表现。每种毒素的PltB亚基表现出不同的聚糖结合偏好，这些偏好与每种细菌在初次感染或中毒部位靶向的宿主细胞的聚糖表达谱相关。通过绑定到特定聚糖受体部分的PltB亚基的共晶体结构，我们表明它们诱导明显不同的聚糖结合偏好和毒力结果。此外，使用NTS S进行免疫。Javiana或其毒素可提供交叉反应性保护，以抵御致命剂量的伤寒毒素攻击。累积地，这些结果提供了对沙门氏菌AB毒素宿主适应性进化，它们的细胞和组织嗜性以及改良伤寒疫苗和治疗剂设计的见解。