Engineered Secretory Immunoglobulin A provides insights on antibody-based effector mechanisms targeting Clostridiodes difficile.
Engineered Secretory Immunoglobulin A provides insights on antibody-based effector mechanisms targeting Clostridiodes difficile.
复制标题
工程分泌型免疫球蛋白 A 提供了有关针对艰难梭菌的基于抗体的效应机制的见解。
DOI：
10.1101/2023.11.08.566291
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Stadtmueller,BethM
中科院分区：
文献类型：
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作者：
Bharathkar,SonyaKumar;Miller,MichaelJ;Stadtmueller,BethM
分泌(S)免疫球蛋白(Ig)A是主要的粘膜抗体，它介导宿主与共生和病原微生物的相互作用，包括艰难梭状芽孢杆菌。SIgA采用由分泌成分(SC)结合的聚合型IgA结构。尽管意义重大，但SIGA如何支持不同的效应器机制的特征很差，基于SIGA的治疗方法也不存在。我们设计了嵌合(C)SIgA，其中我们用单域抗体或单体荧光蛋白取代了SC结构域D2，使我们能够研究和增强SIgA效应机制。CSIgA表现出对艰难梭菌毒素的中和能力增强，促进细菌聚集和细胞破裂，并降低细胞毒性。Csiga还允许我们可视化和/或量化艰难梭菌的形态变化和聚集事件。结果揭示了SIgA对抗艰难梭菌感染的机制，证明了csigA设计可以调节这些机制，并证明了csigA对可能针对广泛抗原和效应器机制的修饰的适应性。
SUMMARY Secretory (S) Immunoglobin (Ig) A is the predominant mucosal antibody, which mediates host interactions with commensal and pathogenic microbes, including Clostridioides difficile. SIgA adopts a polymeric IgA structure that is bound by secretory component (SC). Despite significance, how SIgA supports diverse effector mechanisms is poorly characterized and SIgA-based therapies nonexistent. We engineered chimeric (c) SIgAs, in which we replaced SC domain D2 with a single domain antibody or a monomeric fluorescent protein, allowing us to investigate and enhance SIgA effector mechanisms. cSIgAs exhibited increased neutralization potency against C. difficile toxins, promoted bacterial clumping and cell rupture, and decreased cytotoxicity. cSIgA also allowed us to visualize and/or quantify C. difficile morphological changes and clumping events. Results reveal mechanisms by which SIgA combats C. difficile infection, demonstrate that cSIgA design can modulate these mechanisms, and demonstrate cSIgA’s adaptability to modifications that might target a broad range of antigens and effector mechanisms.