Wang Tianyin, Quijada Darla, Ahmenda Taha, Castillo Jennie Ruelas, Naji Nour Sabiha, Peske J David, Karakousis Petros C, Paul Suman, Karantanos Theodoros, Karanika Styliani
bioRxiv. 2024 Sep 25:2024.09.23.614576. doi: 10.1101/2024.09.23.614576.
Tuberculosis (TB) remains among the leading infectious causes of death. Due to the limited number of antimicrobials in the TB drug discovery pipeline, interest has developed in host-directed approaches to improve TB treatment outcomes. C-C motif chemokine-like receptor 2 (CCRL2) is a unique seven-transmembrane domain receptor that is upregulated by inflammatory signals and mediates leucocyte migration. However, little is known about its role in the setting of TB infection. Here, we show that (Mtb) infection increases CCRL2 protein expression in macrophages and in mouse lungs. To target selectively CCRL2-expressing cells we developed a novel mouse anti-CCRL2 antibody-drug conjugate (ADC) linked with the cytotoxic drug SG3249. We tested its adjunctive therapeutic efficacy against TB when combined with the first-line regimen for drug-susceptible TB (isoniazid, rifampin, pyrazinamide, ethambutol; RHZE). The anti-CCRL2 ADC treatment potentiated RHZE efficacy in Mtb-infected mice and decreased gross lung inflammation. CCRL2 expression in lung dendritic cells and alveolar macrophages was lower in mice receiving anti-CCRL2 ADC treatment + RHZE compared to those receiving RHZE alone or the control group, although the total innate cell populations did not differ across treatment groups. Interestingly, neutrophils were completely absent in the anti-CCRL2 ADC treatment + RHZE group, unlike in the other treatment groups. IFN-γ+ and IL17-Α+ T-cell responses, which are associated with optimal TB control, were also elevated in the anti-CCRL2 ADC treatment + RHZE group. Collectively, our findings suggest that CCRL2-targeting approaches may improve TB treatment outcomes, possibly through selective killing of Mtb-infected innate immune cells.
结核病（TB）仍然是主要的感染性死亡原因之一。由于结核病药物研发管道中的抗菌药物数量有限，人们对通过宿主导向方法改善结核病治疗效果的兴趣日益浓厚。C-C基序趋化因子样受体2（CCRL2）是一种独特的七跨膜结构域受体，受炎症信号上调并介导白细胞迁移。然而，其在结核病感染背景下的作用尚不清楚。在此，我们表明结核分枝杆菌（Mtb）感染会增加巨噬细胞和小鼠肺中CCRL2蛋白的表达。为了选择性靶向表达CCRL2的细胞，我们开发了一种与细胞毒性药物SG3249连接的新型小鼠抗CCRL2抗体药物偶联物（ADC）。我们测试了其与药物敏感结核病一线治疗方案（异烟肼、利福平、吡嗪酰胺、乙胺丁醇；RHZE）联合使用时对结核病的辅助治疗效果。抗CCRL2 ADC治疗增强了RHZE在Mtb感染小鼠中的疗效，并减轻了肺部的严重炎症。与单独接受RHZE或对照组的小鼠相比，接受抗CCRL2 ADC治疗+RHZE的小鼠肺树突状细胞和肺泡巨噬细胞中的CCRL2表达较低，尽管各治疗组的先天细胞总数没有差异。有趣的是，与其他治疗组不同，抗CCRL2 ADC治疗+RHZE组中完全没有中性粒细胞。与最佳结核病控制相关的IFN-γ +和IL17-α + T细胞反应在抗CCRL2 ADC治疗+RHZE组中也有所升高。总体而言，我们的研究结果表明，靶向CCRL2的方法可能改善结核病治疗效果，可能是通过选择性杀死感染Mtb的先天免疫细胞实现的。
