Protein nanovaccine confers robust immunity against Toxoplasma.
Protein nanovaccine confers robust immunity against Toxoplasma.
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DOI：
10.1038/s41541-017-0024-6
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发表时间：
2017
期刊：
影响因子：
9.2
通讯作者：
McLeod R
中科院分区：
文献类型：
--
作者：
El Bissati K;Zhou Y;Paulillo SM;Raman SK;Karch CP;Roberts CW;Lanar DE;Reed S;Fox C;Carter D;Alexander J;Sette A;Sidney J;Lorenzi H;Begeman IJ;Burkhard P;McLeod R
我们设计并制备了一种自组装蛋白质纳米颗粒。这种自组装蛋白纳米颗粒含有来自弓形虫生命周期中表达的抗原的5个CD 8 + HLA-A03-11超型限制性表位、通用CD 4 + T细胞表位PADRE和作为支架和TLR 5激动剂的鞭毛蛋白。这些CD 8 + T细胞表位通过N/KAAA间隔区分开，并针对蛋白酶体切割进行优化。以TLR 4配体-乳剂GLA-SE为佐剂的自组装蛋白纳米粒诱导IFN-γ应答和保护HLA-A*1101转基因小鼠对抗T.刚地。使用自组装蛋白纳米颗粒-GLA-SE免疫，活化CD 8 + T细胞以产生IFN-γ。自组装蛋白纳米颗粒-GLA-SE还保护HLA-A*1101转基因小鼠免受随后的II型寄生虫攻击。因此，将CD 8 + T细胞诱导肽和PADRE组合成形成纳米颗粒的多表位蛋白，与GLA-SE一起施用，导致主要组织相容性复合物I类和II类分子的有效呈递。此外，这些结果表明，TLR 4和TLR 5的激活可能有助于开发诱导T细胞的疫苗，以预防人类弓形虫病。 弓形虫是世界上最常见的寄生虫感染。它会导致大脑和眼睛损伤以及死亡。这种生物存在于全世界大约20亿人的大脑中。虽然活动性感染可以治疗，但无法治愈。疫苗是非常需要的。在此，我们证明，我们可以产生一个自组装蛋白纳米颗粒（SAPN）与鞭毛蛋白作为TLR 5配体免疫刺激信号，并作为支架的CD 8+和CD 4 + T细胞诱导表位。我们发现这种免疫原在我们的人类HLA I类转基因小鼠模型中具有强大的保护作用。我们的SAPN含有通过来自转基因小鼠的CD 8 + T淋巴细胞以及通过CD 4 + T细胞引发IFN-γ产生的肽。用TLR 4配体进一步佐剂化所述SAPN。我们的佐剂，免疫有义SAPN结合了先天性和适应性免疫的刺激，在疫苗开发方面取得了进展，对预防感染具有相当大的希望。
We designed and produced a self-assembling protein nanoparticle. This self-assembling protein nanoparticle contains five CD8+ HLA-A03-11 supertypes-restricted epitopes from antigens expressed during Toxoplasma gondii’s lifecycle, the universal CD4+ T cell epitope PADRE, and flagellin as a scaffold and TLR5 agonist. These CD8+ T cell epitopes were separated by N/KAAA spacers and optimized for proteasomal cleavage. Self-assembling protein nanoparticle adjuvanted with TLR4 ligand-emulsion GLA-SE were evaluated for their efficacy in inducing IFN-γ responses and protection of HLA-A*1101 transgenic mice against T. gondii. Immunization, using self-assembling protein nanoparticle-GLA-SE, activated CD8+ T cells to produce IFN-γ. Self-assembling protein nanoparticle-GLA-SE also protected HLA-A*1101 transgenic mice against subsequent challenge with Type II parasites. Hence, combining CD8+ T cell-eliciting peptides and PADRE into a multi-epitope protein that forms a nanoparticle, administered with GLA-SE, leads to efficient presentation by major histocompatibility complex Class I and II molecules. Furthermore, these results suggest that activation of TLR4 and TLR5 could be useful for development of vaccines that elicit T cells to prevent toxoplasmosis in humans. Toxoplasma gondii is the most common parasitic infection worldwide. It causes brain and eye damage as well as death. The organism is present in the brain of approximately two billion people worldwide. Although active infection can be treated, there is no cure. A vaccine is greatly needed. Herein, we demonstrate that we can produce a self-assembling protein nanoparticle (SAPN) with flagellin as a TLR5 ligand immune stimulating signal, and as a scaffold for CD8+ and CD4+ T cell-eliciting epitopes. We find this immunogen confers robust protection in our human HLA class I transgenic mouse model. Our SAPN contains peptides that elicit production of IFN-γ by CD8+ T lymphocytes from transgenic mice, as well as by CD4+ T cells. The SAPNs are further adjuvanted with a TLR4 ligand. Our adjuvanted, immunosense SAPN that combines stimuli for innate and adaptive immunity, presents an advancement in vaccine development that has considerable promise for protection against infections.
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影响因子：
2.7
作者：
Cong, Hua;Mui, Ernest J.;Witola, William H.;Sidney, John;Alexander, Jeff;Sette, Alessandro;Maewal, Ajesh;El Bissati, Kamal;Zhou, Ying;Suzuki, Yasuhiro;Lee, Daniel;Woods, Stuart;Sommerville, Caroline;Henriquez, Fiona L.;Roberts, Craig W.;McLeod, Rima
通讯作者：
McLeod, Rima
影响因子：
6.7
作者：
Lindestam Arlehamn CS;McKinney DM;Carpenter C;Paul S;Rozot V;Makgotlho E;Gregg Y;van Rooyen M;Ernst JD;Hatherill M;Hanekom WA;Peters B;Scriba TJ;Sette A
通讯作者：
Sette A
影响因子：
5.8
作者：
Anderson, Ryan C.;Fox, Christopher B.;Vedvick, Thomas S.
通讯作者：
Vedvick, Thomas S.
影响因子：
5.4
作者：
de Alwis, Ruklanthi;Bangs, Derek J.;Weiskopf, Daniela
通讯作者：
Weiskopf, Daniela
影响因子：
8
作者：
El Bissati, Kamal;Chentoufi, Aziz A.;McLeod, Rima
通讯作者：
McLeod, Rima