Immune Targeting of Mycobacteria through Cell Surface Glycan Engineering
Immune Targeting of Mycobacteria through Cell Surface Glycan Engineering
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DOI：
10.1021/acschembio.3c00155
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发表时间：
2023-06-12
影响因子：
4
通讯作者：
Swarts，Benjamin M. M.
中科院分区：
文献类型：
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作者：
Dzigba，Priscilla;Rylski，Adrian K. K.;Swarts，Benjamin M. M.
分枝杆菌和分枝杆菌目中的其他生物引起一系列重大人类疾病，包括结核病、麻风病、白喉、布鲁里溃疡和非结核分枝杆菌（NTM）疾病。然而，分枝杆菌细胞包膜产生的内在耐药性破坏了传统的抗生素治疗并导致获得性耐药性。出于通过新的治疗方法增强抗生素的需求，我们开发了一种策略，用抗体招募分子（ARM）特异性修饰分枝杆菌细胞表面聚糖，该分子标记细菌与人内源性抗体结合，从而增强巨噬细胞效应器功能。合成了由海藻糖靶向部分和二硝基苯基半抗原 (Tre-DNP) 组成的分枝杆菌特异性 ARM，并显示可通过海藻糖代谢特异性掺入耻垢分枝杆菌的外膜糖脂中，从而能够将抗 DNP 抗体募集到分枝杆菌细胞表面。 Tre-DNP 修饰的 M 的吞噬作用。在抗 DNP 抗体存在的情况下，巨噬细胞的包皮垢显着增强，这证明了我们的策略可以增强宿主免疫反应的概念验证。由于负责 Tre-DNP 细胞表面掺入的代谢途径在所有分枝杆菌生物体中都是保守的，但在其他细菌和人类中不存在，因此所报告的工具可用于询问宿主与病原体的相互作用并开发针对不同分枝杆菌病原体的免疫靶向策略。
Mycobacteria and other organisms in the order Mycobacteriales cause a range of significant human diseases, including tuberculosis, leprosy, diphtheria, Buruli ulcer, and non-tuberculous mycobacterial (NTM) disease. However, the intrinsic drug tolerance engendered by the mycobacterial cell envelope undermines conventional antibiotic treatment and contributes to acquired drug resistance. Motivated by the need to augment antibiotics with novel therapeutic approaches, we developed a strategy to specifically decorate mycobacterial cell surface glycans with antibody-recruiting molecules (ARMs), which flag bacteria for binding to human-endogenous antibodies that enhance macrophage effector functions. Mycobacterium-specific ARMs consisting of a trehalose targeting moiety and a dinitrophenyl hapten (Tre-DNPs) were synthesized and shown to specifically incorporate into outer-membrane glycolipids ofMycobacterium smegmatisvia trehalose metabolism, enabling recruitment of anti-DNP antibodies to the mycobacterial cell surface. Phagocytosis of Tre-DNP-modifiedM. smegmatisby macrophages was significantly enhanced in the presence of anti-DNP antibodies, demonstrating proof-of-concept that our strategy can augment the host immune response. Because the metabolic pathways responsible for cell surface incorporation of Tre-DNPs are conserved in all Mycobacteriales organisms but absent from other bacteria and humans, the reported tools may be enlisted to interrogate host–pathogen interactions and develop immune-targeting strategies for diverse mycobacterial pathogens.