Laboratory of Genomics and Proteomics of Disease Vectors, Biology Centre CAS, Institute of Parasitology, Branišovská 1160/31, 37005, České Budějovice, Czech Republic.
Department of Medical Biology, Faculty of Science, University of South Bohemia in České Budějovice, Branišovská 1760c, 37005, České Budějovice, Czech Republic.
Cell Mol Life Sci. 2019 May;76(10):2003-2013. doi: 10.1007/s00018-019-03034-3. Epub 2019 Feb 12.
To successfully feed, ticks inject pharmacoactive molecules into the vertebrate host including cystatin cysteine protease inhibitors. However, the molecular and cellular events modulated by tick saliva remain largely unknown. Here, we describe and characterize a novel immunomodulatory cystatin, Iristatin, which is upregulated in the salivary glands of feeding Ixodes ricinus ticks. We present the crystal structure of Iristatin at 1.76 Å resolution. Purified recombinant Iristatin inhibited the proteolytic activity of cathepsins L and C and diminished IL-2, IL-4, IL-9, and IFN-γ production by different T-cell populations, IL-6 and IL-9 production by mast cells, and nitric oxide production by macrophages. Furthermore, Iristatin inhibited OVA antigen-induced CD4 T-cell proliferation and leukocyte recruitment in vivo and in vitro. Our results indicate that Iristatin affects wide range of anti-tick immune responses in the vertebrate host and may be exploitable as an immunotherapeutic.
为了成功进食，蜱虫会向脊椎动物宿主注入具有药理活性的分子，包括半胱氨酸蛋白酶抑制剂。然而，蜱虫唾液调节的分子和细胞事件在很大程度上仍然未知。在这里，我们描述并鉴定了一种新型免疫调节半胱氨酸蛋白酶抑制剂，即 Iristatin，它在进食的蓖子硬蜱的唾液腺中上调。我们呈现了 Iristatin 的晶体结构，分辨率为 1.76 Å。纯化的重组 Iristatin 抑制组织蛋白酶 L 和 C 的蛋白水解活性，并减少不同 T 细胞群产生的 IL-2、IL-4、IL-9 和 IFN-γ、肥大细胞产生的 IL-6 和 IL-9 以及巨噬细胞产生的一氧化氮。此外，Iristatin 抑制体内和体外 OVA 抗原诱导的 CD4 T 细胞增殖和白细胞募集。我们的结果表明，Iristatin 影响脊椎动物宿主中广泛的抗蜱免疫反应，并且可能作为免疫治疗剂被利用。
