A long duration of treatment and emerging drug resistance pose significant challenges for global tuberculosis (TB) eradication efforts. Therefore, there is an urgent need to develop novel strategies to shorten TB treatment regimens and to treat drug-resistant TB. Using an albumin-fusion strategy, we created a novel albumin-fused granulocyte-macrophage colony-stimulating factor (albGM-CSF) molecule that harnesses albumin's long half-life and targeting abilities to enhance the biostability of GM-CSF and direct it to the lymph nodes, where the effects of GM-CSF can increase dendritic cell populations crucial for eliciting a potent immune response. In this study, we demonstrate that albGM-CSF serves as a novel immunotherapy for chronic Mycobacterium tuberculosis (Mtb) infections by enhancing GM-CSF biostability in serum. Specifically, albumin is very safe, stable, and has a long half-life, thereby enhancing the biostability of GM-CSF. In the lungs and draining lymph nodes, albGM-CSF is able to increase the numbers of dendritic cells, which are crucial for the activation of naive T cells and for eliciting potent immune responses. Subcutaneous administration of albGM-CSF alone reduced the mean lung bacillary burden in mice with chronic tuberculosis infection. While GM-CSF administration was associated with IL-1β release from Mtb-infected dendritic cells and macrophages, higher IL-1β levels were observed in albGM-CSF-treated mice with chronic tuberculosis infection than in mice receiving GM-CSF. Albumin fusion with GM-CSF represents a promising strategy for the control of chronic lung tuberculosis infections and serves as a novel therapeutic vaccination platform for other infectious diseases and malignancies.

中文翻译：

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白蛋白与粒细胞-巨噬细胞集落刺激因子融合可作为慢性结核病的免疫疗法。

长期治疗和新出现的耐药性对全球结核病 (TB) 根除工作构成重大挑战。因此，迫切需要制定新的策略来缩短结核病治疗方案并治疗耐药结核病。使用白蛋白融合策略，我们创造了一种新的白蛋白融合粒细胞-巨噬细胞集落刺激因子 (albGM-CSF) 分子，该分子利用白蛋白的长半衰期和靶向能力来增强 GM-CSF 的生物稳定性并将其引导至淋巴结，GM-CSF 的作用可以增加树突状细胞数量，这对于引发有效的免疫反应至关重要。在这项研究中，我们证明 albGM-CSF 通过增强血清中 GM-CSF 的生物稳定性，作为慢性结核分枝杆菌 (Mtb) 感染的新型免疫疗法。具体来说，白蛋白非常安全、稳定、半衰期长，从而增强了GM-CSF的生物稳定性。在肺和引流淋巴结中，albGM-CSF 能够增加树突状细胞的数量，这对于激活幼稚 T 细胞和引发有效的免疫反应至关重要。单独皮下给药 albGM-CSF 可降低慢性结核感染小鼠的平均肺细菌负荷。虽然 GM-CSF 给药与 Mtb 感染的树突状细胞和巨噬细胞释放 IL-1β 相关，但在 albGM-CSF 治疗的慢性结核感染小鼠中观察到的 IL-1β 水平高于接受 GM-CSF 的小鼠。