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IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine Pub Date : 2024-12-12 DOI:10.1016/j.cyto.2024.156832

Bongani Motaung, Candice Snyders, Stephanus Malherbe, Andrea Gutschmidt, Ilana van Rensburg, Andre G Loxton

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引用次数: 0

摘要

尽管抗结核（TB）治疗方法很容易获得，但结核分枝杆菌（Mtb）感染仍然是一个全球性威胁，单一传染源造成的死亡率很高。这凸显了开发新战略以遏制不断增长的 Mtb 感染病例的重要性。宿主导向疗法（HDT）提供了一种前景广阔的方法，它包括药物发现和药物再利用，旨在确定宿主靶点和促进免疫细胞群，从而改善感染结果。在这种情况下，我们利用健康人（QFN-）和暴露于 Mtb 的人 (QFN+) 的 PBMCs，研究了外源性结合免疫球蛋白 (BiP) 在体内诱导这种变化的潜力。我们分析了八种不同刺激条件下的细胞表面表达和细胞因子谱，包括人全长 BiP 蛋白（20 μg/ml）、TLR-9a（0.5 μM）、BiP/TLR-9a 组合、异烟肼（1 μM）、H37Rv（MOI：1：10），以及在肺结核诊断（TBdx）和抗结核治疗第 6 个月（M6）时收集的支气管肺泡灌洗液（BAL）样本。我们的结果显示，BiP 刺激的 PBMCs 白细胞介素（IL）-10 分泌显著减少，IL-4、IL-5、IL-13 和可溶性 Fas-L （sFasL）分泌增加。我们还观察到，在从 QFN- 组和 QFN+ 组分离的 B 细胞中，BiP 刺激增强了膜结合 Fas-L（CD178）和 IL5Ra（CD125）的表达。此外，BiP 与 TLR-9a 具有协同作用，进一步提高了这种共表达。此外，我们还观察到 BiP 可诱导 CD3+CD5lo 和 CD3+CD5hi T 细胞群中 IL5Ra 的表达。本研究探讨了外源 BiP 对细胞功能的影响，并就其调节宿主细胞反应的潜力提供了有价值的见解。

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Exogenous binding immunoglobulin protein (BiP) enhance immune regulatory phenotype in ex-vivo Mtb infected PBMCs stratified based on QuantiFERON response.

Even though anti-tuberculosis (TB) treatment is readily available, Mycobacterium tuberculosis (Mtb) infection continues to be a global threat with a high death rate recorded from a single infectious agent. This highlights the significance of developing new strategies to curb the growing Mtb infection cases. Host-directed therapies (HDT) offer a promising approach that includes both drug discovery and drug repurposing, aimed at identifying host targets and promoting immune cell populations that can lead to better infection outcomes. In this context, we investigated the potential of exogenous Binding Immunoglobulin Protein (BiP) to induce such changes ex-vivo using PBMCs from healthy (QFN-) and Mtb exposed (QFN+) individuals. We analysed cell surface expression and cytokine profiles across eight different stimulation conditions including human full-length BiP protein (20 μg/ml), TLR-9a (0.5 μM), BiP/TLR-9a combination, isoniazid (1 μM), H37Rv (MOI: 1: 10), and pooled bronchoalveolar lavage (BAL) samples collected at TB diagnosis (TBdx) and at month 6 (M6) of anti-TB treatment. Our results revealed that BiP-stimulated PBMCs showed a significant reduction of interleukin (IL)-10 secretion, along with increased IL-4, IL-5, IL-13, and soluble Fas-L (sFasL) secretion. We also observed that BiP stimulation enhanced the expression of membrane bound Fas-L (CD178) and IL5Ra (CD125) in B-cells isolated from both QFN- and QFN+ groups. Additionally, BiP exhibited a synergistic effect with TLR-9a, further boosting this co-expression. Moreover, we observed that BiP induced IL5Ra expression in both CD3⁺CD5^lo and CD3⁺CD5^hi T-cell populations. This study explores the effects of exogenous BiP on cell functionality and provides valuable insights into its potential to modulate host cell responses, which could be explored as a host-directed therapy for TB in the future.

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来源期刊

Cytokine 医学-免疫学

CiteScore

7.60

自引率

2.60%

发文量

262

审稿时长

48 days

期刊介绍： The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.