Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy.
Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy.
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DOI：
10.1016/j.biomaterials.2016.03.039
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发表时间：
2016-08
期刊：
影响因子：
14
通讯作者：
Fahmy TM
中科院分区：
文献类型：
--
作者：
Siefert AL;Caplan MJ;Fahmy TM
抗原提呈细胞(APC)通过细胞外和细胞内的Toll样受体(TLRs)通过病原体相关分子模式(PAMPs)感知微生物，启动对入侵病原体的免疫反应。细菌PAMP包括胞外脂多糖和胞内未甲基化的富含CpG的寡核苷酸(CpG)。我们推测，一种利用展示单磷酰脂A(MPLA)的抗原负载纳米颗粒(NP)和包裹CpG的仿生方法可能作为一种有效的“人工细菌”仿生疫苗平台发挥作用。利用可生物降解的聚乳酸-乙醇酸(PLGA)聚合物组装的NP，表面修饰MPLA，负载CpG和模型抗原卵白蛋白(OVA)，在体外和体内验证了这一假说。首先，与同等浓度的表面呈现的CpG相比，当CpG被包裹在NP中时，CpG的效力(以细胞因子谱、滴度和抗原特异性T细胞反应为特征)得到增强，突显了PAMP仿生呈现的重要性。第二，与单一的PAMP或可溶性的PAMP组合相比，NP在体外和体内协同表面结合的MPLA和包裹的CpG，诱导更大的促炎、抗原特异性T辅助1(Th1)偏斜的细胞和抗体介导的反应。重要的是，CpG和MPLA的NP共提呈对CD8+T细胞反应至关重要，因为无论是CpG还是Mpla的NP混合物接种都不能诱导细胞免疫。这项工作展示了一种合理的方法，用于以上下文相关的方式结合TLR配体，用于协同纳米颗粒疫苗。
Antigen-presenting cells (APCs) sense microorganisms via pathogen-associated molecular patterns (PAMPs) by both extra- and intracellular Toll-like Receptors (TLRs), initiating immune responses against invading pathogens. Bacterial PAMPs include extracellular lipopolysaccharides and intracellular unmethylated CpG-rich oligodeoxynucleotides (CpG). We hypothesized that a biomimetic approach involving antigen-loaded nanoparticles (NP) displaying Monophosphoryl Lipid A (MPLA) and encapsulating CpG may function as an effective “artificial bacterial” biomimetic vaccine platform. This hypothesis was tested in vitro and in vivo using NP assembled from biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer, surface-modified with MPLA, and loaded with CpG and model antigen Ovalbumin (OVA). First, CpG potency, characterized by cytokine profiles, titers, and antigen-specific T cell responses, was enhanced when CpG was encapsulated in NP compared to equivalent concentrations of surface-presented CpG, highlighting the importance of biomimetic presentation of PAMPs. Second, NP synergized surface-bound MPLA with encapsulated CpG in vitro and in vivo, inducing greater pro-inflammatory, antigen-specific T helper 1 (Th1)-skewed cellular and antibody-mediated responses compared to single PAMPs or soluble PAMP combinations. Importantly, NP co-presentation of CpG and MPLA was critical for CD8+ T cell responses, as vaccination with a mixture of NP presenting either CpG or MPLA failed to induce cellular immunity. This work demonstrates a rational methodology for combining TLR ligands in a context-dependent manner for synergistic nanoparticulate vaccines.