Aluminum hydroxide adjuvant diverts the uptake and trafficking of genetically detoxified pertussis toxin to lysosomes in macrophages,Molecular Microbiology

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Aluminum hydroxide adjuvant diverts the uptake and trafficking of genetically detoxified pertussis toxin to lysosomes in macrophages
Molecular Microbiology ( IF 2.6 ) Pub Date : 2022-03-28 , DOI: 10.1111/mmi.14900
Javier Jaldin-Fincati ₁ , Serene Moussaoui _{1,

2} , Maria Cecilia Gimenez ₁ , Cheuk Y Ho ₁ , Charlene E Lancaster _{1,

2} , Roberto Botelho ₃ , Fernando Ausar ₄ , Roger Brookes ₄ , Mauricio Terebiznik _{1,

2}

Affiliation

Aluminum salts have been successfully utilized as adjuvants to enhance the immunogenicity of vaccine antigens since the 1930s. However, the cellular mechanisms behind the immune adjuvanticity effect of these materials in antigen-presenting cells are poorly understood. In this study, we investigated the uptake and trafficking of aluminum oxy-hydroxide (AlOOH), in RAW 264.7 murine and U-937 human macrophages-like cells. Furthermore, we determined the impact that the adsorption to AlOOH particulates has on the trafficking of a Bordetella pertussis vaccine candidate, the genetically detoxified pertussis toxin (gdPT). Our results indicate that macrophages internalize AlOOH by constitutive macropinocytosis assisted by the filopodial protrusions that capture the adjuvant particles. Moreover, we show that AlOOH has the capacity to nonspecifically adsorb IgG, engaging opsonic phagocytosis, which is a feature that may allow for more effective capture and uptake of adjuvant particles by antigen-presenting cells (APCs) at the site of vaccine administration. We found that AlOOH traffics to endolysosomal compartments that hold degradative properties. Importantly, while we show that gdPT escapes degradative endolysosomes and traffics toward the retrograde pathway, as reported for the wild-type pertussis toxin, the adsorption to AlOOH diverts gdPT to traffic to the adjuvant’s lysosome-type compartments, which may be key for MHC-II-driven antigen presentation and activation of CD4⁺ T cell. Thus, our findings establish a direct link between antigen adsorption to AlOOH and the intracellular trafficking of antigens within antigen-presenting cells and bring to light a new potential mechanism for aluminum adjuvancy. Moreover, the in-vitro single-cell approach described herein provides a general framework and tools for understanding critical attributes of other vaccine formulations.

中文翻译：

氢氧化铝佐剂将遗传解毒的百日咳毒素的摄取和运输转移到巨噬细胞中的溶酶体

自 1930 年代以来，铝盐已成功用作佐剂以增强疫苗抗原的免疫原性。然而，这些材料在抗原呈递细胞中的免疫佐剂效应背后的细胞机制知之甚少。在这项研究中，我们研究了 RAW 264.7 鼠和 U-937 人巨噬细胞样细胞中氢氧化铝 (AlOOH) 的摄取和运输。此外，我们确定了对 AlOOH 颗粒的吸附对百日咳博德特氏菌运输的影响候选疫苗，基因解毒百日咳毒素（gdPT）。我们的结果表明，巨噬细胞通过在捕获佐剂颗粒的丝状突起辅助下组成性巨胞饮作用将 AlOOH 内化。此外，我们表明，AlOOH 具有非特异性吸附 IgG 的能力，参与调理吞噬作用，这一特征可能允许疫苗给药部位的抗原呈递细胞 (APC) 更有效地捕获和摄取佐剂颗粒。我们发现 AlOOH 会进入具有降解特性的内溶酶体隔室。重要的是，虽然我们证明 gdPT 逃离降解的内溶酶体并朝着逆行途径运输，正如野生型百日咳毒素所报道的那样，但吸附到 AlOOH 后 gdPT 转移到佐剂的溶酶体型隔室，⁺ T 细胞。因此，我们的研究结果建立了抗原吸附到 AlOOH 与抗原呈递细胞内抗原的细胞内运输之间的直接联系，并揭示了铝佐剂的新潜在机制。此外，本文所述的体外单细胞方法提供了用于理解其他疫苗制剂的关键属性的通用框架和工具。

更新日期：2022-03-28

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