TLR4 Ligands in Typhoid Vi Polysaccharide Subunit Vaccines Contribute to Immunogenicity.
TLR4 Ligands in Typhoid Vi Polysaccharide Subunit Vaccines Contribute to Immunogenicity.
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DOI：
10.4049/immunohorizons.2300085
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发表时间：
2024-01-01
期刊：
影响因子：
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通讯作者：
Alugupalli KR
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文献类型：
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作者：
Alugupalli KR
B细胞和T细胞的激活需要共刺激信号通路的参与，除了Ag受体信号外，还需要有效的免疫反应。伤寒Vi多糖(VIPS)亚单位疫苗中没有一种含有能够激活共刺激信号通路的佐剂，但这些疫苗具有很强的免疫原性。我推测，用于制造伤寒亚单位疫苗的VIPS制剂中存在的残留TLR配体是这些疫苗产生强大免疫反应的原因。我展示了VIPS制剂和VIPS疫苗中存在内毒素，它是TLR4的一种强有力的激动剂。此外，我发现从不同来源获得的VIP可以诱导小鼠腹膜渗出细胞产生促炎细胞因子，如IL-6。未结合和破伤风类毒素结合的VIPs疫苗激活人和小鼠TLR4。TLR4或信号适配器MyD88和TRIF(Toll/IL-1R结构域适配器诱导干扰素-β)缺陷的小鼠在对这些疫苗产生抗VIPS反应方面受到严重损害。清除VIPS制剂中的TLR4激动剂会导致免疫原性的丧失，而添加已知的TLR4激动剂脂质A可恢复免疫原性。这些数据突显了相关的TLR配体在VIPS亚单位疫苗免疫原性中的重要性。
Activation of B cells and T cells requires the engagement of costimulatory signaling pathways in addition to Ag receptor signaling for efficient immune responses. None of the typhoid Vi polysaccharide (ViPS) subunit vaccines contains adjuvants that could activate costimulatory signaling pathways, yet these vaccines are very immunogenic. I hypothesized that residual TLR ligands present in the ViPS preparation used for making typhoid subunit vaccines account for the robust immune response generated by these vaccines. I show the presence of endotoxin, a potent agonist of TLR4, in ViPS preparations and ViPS vaccines. Furthermore, I found that ViPS obtained from various sources induces the production of proinflammatory cytokines such as IL-6 from mouse peritoneal exudate cells. Unconjugated and tetanus toxoid–conjugated ViPS vaccines activate human and mouse TLR4. Mice deficient in TLR4 or the signaling adaptors MyD88 and Trif (Toll/IL-1R domain–containing adapter inducing IFN-β) are severely impaired in generating anti-ViPS responses to these vaccines. Elimination of the TLR4 agonist in ViPS preparation resulted in the loss of immunogenicity, and addition of lipid A, a known TLR4 agonist, restored the immunogenicity. These data highlight the importance of associated TLR ligands in the immunogenicity of ViPS subunit vaccines.