PDF(Pubmed)
Abstract：
Cystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in activating the perforin/granzyme cytotoxic pathways. It is targeted at the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CstF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loads. In human macrophages, our previous results revealed a strong upregulation of CstF in phagocytes activated by interferon γ or after infection with Mycobacterium tuberculosis (Mtb). CstF manipulation using RNA silencing led to increased proteolytic activity of lysosomal cathepsins, improving Mtb intracellular killing. In the present work, we investigate the impact of CstF depletion in macrophages during the coinfection of Mtb-infected phagocytes with lymphocytes infected with HIV. The results indicate that decreasing the CstF released by phagocytes increases the major pro-granzyme convertase cathepsin C of cytotoxic immune cells from peripheral blood-derived lymphocytes. Consequently, an observed augmentation of the granzyme B cytolytic activity leads to a significant reduction in viral replication in HIV-infected CD4+ T-lymphocytes. Ultimately, this knowledge can be crucial for developing new therapeutic approaches to control both pathogens based on manipulating CstF.
摘要：
胱抑素F（CstF）是半胱氨酸组织蛋白酶的蛋白酶抑制剂，包括参与激活穿孔素/颗粒酶细胞毒性途径的那些。它靶向内溶酶体途径,但也可以分泌到细胞外环境或被旁观者细胞内吞。CstF在结核性胸膜炎中显示显着增加，在艾滋病毒合并感染期间，胸膜液显示高病毒载量.在人类巨噬细胞中，我们先前的结果表明，在干扰素γ激活的吞噬细胞中或感染结核分枝杆菌（Mtb）后，CstF强烈上调。使用RNA沉默的CstF操作导致溶酶体组织蛋白酶的蛋白水解活性增加，提高Mtb细胞内杀伤。在目前的工作中,我们研究了在Mtb感染的吞噬细胞与HIV感染的淋巴细胞共感染过程中巨噬细胞中CstF耗竭的影响。结果表明，减少吞噬细胞释放的CstF会增加来自外周血衍生淋巴细胞的细胞毒性免疫细胞的主要粒前酶转化酶组织蛋白酶C。因此,观察到的颗粒酶B细胞溶解活性的增强导致HIV感染的CD4+T淋巴细胞中病毒复制的显著减少.最终,这些知识对于开发基于操纵CstF控制两种病原体的新治疗方法至关重要。
