Department of Infectious Disease, Imperial College London, London, United Kingdom.
Leishmaniasis Research and Treatment Centre, University of Gondar, Gondar, Ethiopia.
PLoS Negl Trop Dis. 2022 Jun 24;16(6):e0010544. doi: 10.1371/journal.pntd.0010544. eCollection 2022 Jun.
Visceral leishmaniasis (VL) is a neglected tropical disease that causes substantial morbidity and mortality and is a growing health problem in Ethiopia, where this study took place. Most individuals infected with Leishmania donovani parasites will stay asymptomatic, but some develop VL that, if left untreated, is almost always fatal. This stage of the disease is associated with a profound immunosuppression, characterised by impaired production of Interferonγ (IFNγ), a cytokine that plays a key role in the control of Leishmania parasites, and high expression levels of an inhibitory receptor, programmed cell death 1 (PD1) on CD4+ T cells. Here, we tested the contribution of the interaction between the immune checkpoint PD1 and its ligand PDL-1 on the impaired production of IFNγ in VL patients. Our results show that in the blood of VL patients, not only CD4+, but also CD8+ T cells express high levels of PD1 at the time of VL diagnosis. Next, we identified PDL-1 expression on different monocyte subsets and neutrophils and show that PDL-1 levels were significantly increased in VL patients. PD1/PDL-1 inhibition resulted in significantly increased production of IFNγ, suggesting that therapy using immune checkpoint inhibitors might improve disease control in these patients.
内脏利什曼病（VL）是一种被忽视的热带病，会导致大量发病和死亡，也是本研究所在的埃塞俄比亚日益严重的健康问题。大多数感染利什曼原虫寄生虫的人将无症状，但有些人会发展为 VL，如果不治疗，几乎总是致命的。这种疾病的阶段与严重的免疫抑制有关，其特征是干扰素γ（IFNγ）的产生受损，IFNγ是一种在控制利什曼寄生虫方面发挥关键作用的细胞因子，以及 CD4+T 细胞上程序性细胞死亡蛋白 1（PD1）的高表达水平。在这里，我们测试了免疫检查点 PD1 与其配体 PDL-1 之间的相互作用对 VL 患者 IFNγ产生受损的贡献。我们的结果表明，在 VL 患者的血液中，不仅 CD4+，而且 CD8+T 细胞在 VL 诊断时都表达高水平的 PD1。接下来，我们确定了不同单核细胞亚群和中性粒细胞上的 PDL-1 表达，并表明 VL 患者的 PDL-1 水平显著增加。PD1/PDL-1 抑制导致 IFNγ的产生显著增加，表明使用免疫检查点抑制剂的治疗可能会改善这些患者的疾病控制。
