Holland-Tummillo Kristen M, Shoudy Lauren E, Steiner Donald, Kumar Sudeep, Rosa Sarah J, Namjoshi Prachi, Singh Anju, Sellati Timothy J, Gosselin Edmund J, Hazlett Karsten Ro
Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA.
Pathogens. 2020 May 14;9(5):375. doi: 10.3390/pathogens9050375.
The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, , , and . Using as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.
在不使用外源性佐剂的情况下，将免疫原/疫苗靶向特定免疫细胞是增强免疫反应的一种有前景的方法。然而，迄今为止报道的靶向方法针对每种疫苗都需要新型的、耗费人力的试剂，并且主要仅在分离的蛋白质和/或灭活细菌中作为概念验证得到展示。我们构建了一种基于质粒的、靶向补体受体的平台，该平台可轻松应用于多种革兰氏阴性菌的活菌体，包括但不限于 、 、 和 。以 作为模型，我们发现靶向细菌显示出被巨噬细胞的结合和摄取增加，这与p38和p65磷酸化增加相吻合。用靶向细菌接种的小鼠产生更高滴度的特异性抗体，该抗体能识别更多种类的细菌抗原。在用同源或异源分离株攻击后，与接种非靶向免疫原的对应小鼠相比，这些小鼠体重减轻更少和/或体重恢复加快。总体而言，这些发现为基于质粒的、对革兰氏阴性菌活菌体进行补体受体靶向提供了概念验证。
