Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India; Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Griffith University, Institute of Glycomics, Gold Coast, QLD, Australia.
Cell Rep. 2020 Feb 25;30(8):2512-2525.e9. doi: 10.1016/j.celrep.2020.01.099.
Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4 T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4 T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4 T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.
I 型干扰素（IFNs）在抗病毒和抗肿瘤免疫中发挥着关键作用。然而，它们在某些传染病中也会抑制保护性免疫反应。在这里，我们发现 I 型 IFNs 是内脏利什曼病（VL）患者 CD4 T 细胞的主要上游调节剂。此外，我们报告说，缺乏 I 型 IFN 信号的小鼠对导致人类 VL 的利什曼原虫有显著更好的控制，这与寄生虫特异性 CD4 T 细胞产生增强的 IFNγ但减少的 IL-10 有关。重要的是，我们鉴定出一种小分子抑制剂，可用于在已建立的感染期间阻断 I 型 IFN 信号，并与传统抗寄生虫药物协同作用，以改善寄生虫清除并增强小鼠和人类的抗寄生虫 CD4 T 细胞反应。因此，操纵 I 型 IFN 信号是改善 VL 患者疾病结局的有前途的策略。
