Redirecting the immune response towards immunoprotective domains of a DNABII protein resolves experimental otitis media.,npj Vaccines

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Redirecting the immune response towards immunoprotective domains of a DNABII protein resolves experimental otitis media.
npj Vaccines ( IF 6.9 ) Pub Date : 2019-10-14 , DOI: 10.1038/s41541-019-0137-1
L A Novotny ₁ , S D Goodman _{1,

2} , L O Bakaletz _{1,

2}

Affiliation

The chronicity and recurrence of many bacterial diseases is largely attributable to the presence of a biofilm, and eradication of these structures is confounded by an extracellular DNA-rich matrix. DNABII proteins, including integration host factor (IHF), are critical components of the matrix formed by all human pathogens tested to date. Whereas the natural adaptive immune response to IHF is against non-protective epitopes within the carboxyl-terminal region, antibodies against the DNA-binding "tips" induce biofilm collapse. We designed a "tip-chimer" immunogen to mimic the DNA-binding regions within the α-subunit and β-subunit of IHF from nontypeable Haemophilus influenzae (IHFNTHi). Re-direction of the natural adaptive immune response toward immunoprotective domains disrupted NTHi biofilms in vitro and in an experimental model of otitis media. Our data support the rational design of a powerful therapeutic approach, and also that of a DNABII-directed vaccine antigen that would avoid augmentation of any pre-existing natural, but nonprotective, immune response.

中文翻译：

将免疫应答重定向至DNABII蛋白的免疫保护域可解决实验性中耳炎。

许多细菌性疾病的慢性和复发在很大程度上归因于生物膜的存在，而根除这些结构的原因是富含细胞外DNA的基质所致。DNABII蛋白，包括整合宿主因子（IHF），是迄今为止所有人类病原体形成的基质的关键成分。对IHF的天然适应性免疫反应是针对羧基末端区域内的非保护性抗原决定簇，而针对DNA结合“尖端”的抗体则诱导生物膜塌陷。我们设计了一种“尖端嵌合体”免疫原，以模拟来自不可分型流感嗜血杆菌（IHFNTHi）的IHFα亚基和β亚基内的DNA结合区域。在免疫性领域的自然适应性免疫反应的重定向在体外和在中耳炎的实验模型中破坏了NTHi生物膜。我们的数据支持合理设计一种有效的治疗方法，以及针对DNABII的疫苗抗原的合理设计，这些抗原可避免增加任何先前存在的天然但无保护性的免疫应答。

更新日期：2019-10-14

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