Effect of tick saliva cystatins on Th9 cells, mast cells and the development of experimental asthma

蜱的唾液中含有一系列免疫调节分子，有助于吸血和蜱传病原体的传播。基于蜱唾液腺cDNA文库，已鉴定并制备了其中的一些分子。蓖麻硬蜱唾液和sialostatin L，一种从相关蜱I唾液中分离的半胱氨酸蛋白酶抑制剂。肩胛肌，令人惊讶地抑制白细胞介素9（IL-9）的产生。由于IL-9在过敏性哮喘的发展中起着核心作用，我们在小鼠哮喘模型的致敏阶段给予唾液酸抑制素L，并在初步实验中发现它抑制了这种疾病的发展。由于我们的初步数据表明，唾液酸抑制素L对肥大细胞和Th 9细胞的IL-9产生具有显著的抑制能力，我们将主要关注这种半胱氨酸蛋白酶抑制剂的抑制机制。特别地，将分析半胱氨酸蛋白酶抑制剂对Th 9细胞和肥大细胞的激酶组的影响。或者，Th 9细胞和肥大细胞的表达谱将在不存在和存在抑制性半胱氨酸蛋白酶抑制剂的情况下通过下一代测序（NGS）来确定。最终，所获得的结果将用于开发创新的治疗策略，通过利用确定的IL-9调节分子从蜱唾液中治疗过敏性疾病和哮喘。

Tick saliva contains an array of immunomodulatory molecules facilitating both blood feeding and tick-borne pathogen transmission. Based on cDNA library of tick salivary glands, some of these molecules have been identified and prepared by recombinant expression. Ixodes ricinus tick saliva and sialostatin L, a cystatin isolated from saliva of the related tick I. scapularis, surprisingly inhibited production of interleukin 9 (IL-9). As IL-9 plays a central role in the development of allergic asthma, we administered sialostatin L during the sensitization phase in a murine asthma model and found in pilot experiments that it inhibits the development of this disease. Since our preliminary data demonstrated that sialostatin L has a substantial inhibitory capacity on the IL-9 production of mast cells and Th9 cells, we will primarily focus on the inhibitory mechanism(s) of such cystatins. Especially, the influence of cystatins on the kinome of Th9 cells and mast cells will be analyzed. Alternatively, expression profiles of Th9 cells and mast cells will be determined by next-generation sequencing (NGS) in the absence and presence of inhibitory cystatins. Eventually, the obtained results will be used to develop innovative therapeutic strategies for the treatment of allergic diseases and asthma by exploiting definite IL-9 modulating molecules from tick saliva.