Protective cellular responses elicited by vaccination with influenza nucleoprotein delivered by a live recombinant attenuated Salmonella vaccine.
Protective cellular responses elicited by vaccination with influenza nucleoprotein delivered by a live recombinant attenuated Salmonella vaccine.
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DOI：
10.1016/j.vaccine.2011.03.066
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发表时间：
2011-05-23
期刊：
影响因子：
5.5
通讯作者：
Curtiss, Roy, III
中科院分区：
文献类型：
--
作者：
Ashraf, Shamaila;Kong, Wei;Wang, Shifeng;Yang, Jiseon;Curtiss, Roy, III
口服重组减毒沙门氏菌疫苗（RASV）可诱导机体产生针对免疫抗原的体液和粘膜免疫应答。开发针对由RASV递送的病毒或细胞内细菌的有效疫苗的挑战是将保护性抗原引入宿主细胞细胞质内以呈递给MHC-I分子，用于有效的细胞介导的免疫应答。为了将流感核蛋白（NP）靶向到宿主细胞胞质溶胶中，我们构建了编码流感NP的体内调节延迟裂解RASV毒株X 11246（pYA 4858），其具有sifA基因的染色体缺失，以使其能够在裂解之前从内体逃逸。用χ11246（pYA 4858）（SifA-）口服免疫小鼠，3次加强免疫，导致对致死性流感病毒（rWSN）攻击（100 LD 50）的完全保护（100%），而用同基因χ11017（pYA 4858）（SifA+）毒株免疫的小鼠的存活率为25%。用χ11246（pYA 4858）加强免疫的次数从3次减少到2次导致用rWSN（100 LD 50）攻击的小鼠的66%存活。经口、鼻内和腹腔内免疫小鼠，χ11246（pYA 4858）对rWSN的保护率分别为80%、100%和100%（100 LD 50）。在所有实验中，针对流感NP引发了Th 1型免疫应答。未发现分泌IFN-γ的NP 147 -155特异性T细胞与保护相关。抗原特异性CD 8 + T细胞的作用仍有待确定。总之，我们表明沙门氏菌可以被设计为将抗原递送至宿主细胞胞质溶胶，用于推测I类呈递，以诱导保护性免疫应答。
Orally administered recombinant attenuated Salmonella vaccines (RASV) elicit humoral and mucosal immune responses against the immunizing antigen. The challenge in developing an effective vaccine against a virus or an intracellular bacterium delivered by RASVs is to introduce the protective antigen inside the host cell cytoplasm for presentation to MHC-I molecules for an efficient cell mediated immune response. To target the influenza nucleoprotein (NP) into the host cell cytosol, we constructed a regulated delayed lysis in vivo RASV strain χ11246(pYA4858) encoding influenza NP with a chromosomal deletion of the sifA gene to enable it to escape from the endosome prior to lysis. Oral immunization of mice with χ11246(pYA4858) (SifA−) with 3 booster immunizations resulted in complete protection (100%) against a lethal influenza virus (rWSN) challenge (100 LD50) compared to 25% survival of mice immunized with the isogenic χ11017(pYA4858) (SifA+) strain. Reducing the number of booster immunizations with χ11246(pYA4858) from 3 to 2 resulted in 66% survival of mice challenged with rWSN (100 LD50). Immunization with χ11246(pYA4858) via different routes provided protection in 80% orally, 100% intranasally and 100% intraperitoneally immunized mice against rWSN (100 LD50). A Th1 type immune response was elicited against influenza NP in all experiments. IFN-γ secreting NP147–155 specific T cells were not found to be correlated with protection. The role of antigen-specific CD8+ T cells remains to be determined. To conclude, we showed that Salmonella can be designed to deliver antigen(s) to the host cell cytosol for presumably class I presentation for the induction of protective immune responses.
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影响因子：
5.5
作者：
Branger CG;Torres-Escobar A;Sun W;Perry R;Fetherston J;Roland KL;Curtiss R 3rd
通讯作者：
Curtiss R 3rd
影响因子：
2.7
作者：
DEBOER, GF;BACK, W;OSTERHAUS, ADME
通讯作者：
OSTERHAUS, ADME
影响因子：
3.1
作者：
Brumell, JH;Tang, P;Finlay, BB
通讯作者：
Finlay, BB
影响因子：
5.4
作者：
Evans, DT;Chen, LM;Johnson, PR
通讯作者：
Johnson, PR
影响因子：
3.2
作者：
HITCHCOCK, PJ;BROWN, TM
通讯作者：
BROWN, TM