Genetically engineered Salmonella Typhimurium are potent vectors for prophylactic and therapeutic measures against pathogens as well as cancer. This is based on the potent adjuvanticity that supports strong immune responses. The physiology of Salmonella is well understood. It simplifies engineering of both enhanced immune-stimulatory properties as well as safety features, thus, resulting in an appropriate balance between attenuation and efficacy for clinical applications. A major virulence factor of Salmonella is the flagellum. It is also a strong pathogen-associated molecular pattern recognized by extracellular and intracellular receptors of immune cells of the host. At the same time, it represents a serious metabolic burden. Accordingly, the bacteria evolved tight regulatory mechanisms that control flagella synthesis in vivo. Here, we systematically investigated the immunogenicity and adjuvant properties of various flagella mutants of Salmonella in vitro and in a mouse cancer model in vivo. We found that mutants lacking the flagellum-specific ATPase FliHIJ or the inner membrane ring FliF displayed the greatest stimulatory capacity and strongest antitumor effects, while remaining safe in vivo. Scanning electron microscopy revealed the presence of outer membrane vesicles in the ΔfliF and ΔfliHIJ mutants. Finally, the combination of the ΔfliF and ΔfliHIJ mutations with our previously described attenuated and immunogenic background strain SF102 displayed strong efficacy against the highly resistant cancer cell line RenCa. We thus conclude that manipulating flagella biosynthesis has great potential for the construction of highly efficacious and versatile Salmonella vector strains.

中文翻译：

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细菌鞭毛在沙门氏菌介导的肿瘤治疗中的免疫原性潜力。

基因工程鼠伤寒沙门氏菌是用于预防和治疗病原体以及癌症的有效载体。这是基于强大的佐剂，可支持强大的免疫反应。沙门氏菌的生理学已广为人知。它简化了增强的免疫刺激特性和安全性特征的工程设计，因此，在临床应用的衰减和功效之间达到了适当的平衡。沙门氏菌的主要毒力因子是鞭毛。它也是一种很强的病原体相关分子模式，可被宿主免疫细胞的细胞外和细胞内受体识别。同时，它代表了严重的代谢负担。因此，细菌进化出严密的调节机制来控制体内鞭毛的合成。这里，我们系统地研究了沙门氏菌的各种鞭毛突变体的体外免疫原性和佐剂特性，以及体内小鼠癌模型中的免疫原性和佐剂特性。我们发现缺少鞭毛特异性ATPase FliHIJ或内膜环FliF的突变体显示出最大的刺激能力和最强的抗肿瘤作用，同时在体内仍保持安全。扫描电子显微镜显示在ΔfliF和ΔfliHIJ突变体中存在外膜囊泡。最后，ΔfliF和ΔfliHIJ突变与我们先前描述的减毒和免疫原性背景菌株SF102的结合显示了对高度耐药的癌细胞系RenCa的强大功效。