Stimulation of Human Dendritic Cells by Wild-Type and M Protein Mutant Vesicular Stomatitis Viruses Engineered To Express Bacterial Flagellin
Stimulation of Human Dendritic Cells by Wild-Type and M Protein Mutant Vesicular Stomatitis Viruses Engineered To Express Bacterial Flagellin
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DOI：
10.1128/jvi.00406-10
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Lyles, Douglas S.
中科院分区：
文献类型：
--
作者：
Ahmed, Maryam;Puckett, Shelby;Lyles, Douglas S.
含有野生型（wt）或突变基质（M）蛋白的水疱性口炎病毒（VSV）由于其诱导先天性和适应性免疫的能力而被开发为候选疫苗载体。具有wt M蛋白的病毒，例如重组野生型（rwt）病毒，通过Toll样受体7（TLR 7）及其衔接分子MyD 88刺激树突状细胞（DC）的成熟。然而，M蛋白突变病毒，如rM 51 R-M病毒，刺激TLR 7阳性和TLR 7阴性DC亚群。本研究的目的是确定rwt和rM 51 R-M病毒诱导人DC成熟的能力是否可以通过工程改造这些载体以表达细菌鞭毛蛋白来增强。从rwt病毒基因组表达的鞭毛蛋白部分保护人DC免受VSV诱导的宿主蛋白合成的阻断，并促进白细胞介素6（IL-6）和IL-1 β的产生。此外，表达鞭毛蛋白的rwt病毒感染的DC在刺激CD 8（+）同种异体T细胞产生γ干扰素（IFN-γ）方面比rwt病毒感染的DC更有效。虽然rM 51 R-M病毒有效地刺激了人DC，但从rM 51 R-M病毒基因组表达的鞭毛蛋白增强了细胞因子的产生。此外，用表达鞭毛蛋白的rwt和rM 51 R-M病毒免疫的小鼠在体内具有增强的抗VSV抗体应答。因此，表达鞭毛蛋白的rwt和rM 51 R-M病毒由于其刺激DC功能的潜力而可能是用于递送外源抗原的有希望的载体。
Vesicular stomatitis viruses (VSVs) containing wild-type (wt) or mutant matrix (M) proteins are being developed as candidate vaccine vectors due to their ability to induce innate and adaptive immunity. Viruses with wt M protein, such as recombinant wild-type (rwt) virus, stimulate maturation of dendritic cells (DC) through Toll-like receptor 7 (TLR7) and its adaptor molecule MyD88. However, M protein mutant viruses, such as rM51R-M virus, stimulate both TLR7-positive and TLR7-negative DC subsets. The goal of this study was to determine whether the ability of rwt and rM51R-M viruses to induce maturation of human DC can be enhanced by engineering these vectors to express bacterial flagellin. Flagellin expressed from the rwt virus genome partially protected human DC from VSV-induced shutoff of host protein synthesis and promoted the production of interleukin 6 (IL-6) and IL-1 beta. In addition, DC infected with rwt virus expressing flagellin were more effective at stimulating gamma interferon (IFN-gamma) production from CD8(+) allogeneic T cells than DC infected with rwt virus. Although rM51R-M virus effectively stimulated human DC, flagellin expressed from the rM51R-M virus genome enhanced the production of cytokines. Furthermore, mice immunized with both rwt and rM51R-M viruses expressing flagellin had enhanced anti-VSV antibody responses in vivo. Therefore, rwt and rM51R-M viruses expressing flagellin may be promising vectors for the delivery of foreign antigen due to their potential to stimulate DC function.