Identification and characterization of host molecules targeted by leishmania donovani cathepsin B and cathepsin L cysteine proteases during leishmania survival and pathogenesis

利什曼原虫是人类利什曼病的病原体。杜氏利什曼原虫复合体导致内脏利什曼病，每年造成50多万新病例和59,000人死亡。尽管已经确定了几种潜在的候选疫苗，但还没有针对利什曼病的疫苗。此外，耐药性的出现是利什曼病控制的另一个主要问题。利什曼原虫调节免疫应答，涉及的寄生虫因子以及调节宿主免疫系统和信号通路的详细机制尚不完全清楚。半胱氨酸蛋白酶是潜在的药物和疫苗候选，与宿主免疫系统和信号通路的调节有关。白介素10和转化生长因子β是利什曼原虫致病过程中为逃避宿主杀菌活动而产生的主要促炎细胞因子。尽管寄生虫半胱氨酸蛋白酶参与了这一过程，但针对的特定宿主分子和详细的机制尚未确定。然而，本实验室已报道了查加西组织蛋白B半胱氨酸蛋白酶在体外裂解前转化生长因子β1而激活转化生长因子1，尽管其在生存和发病机制中的意义尚未确定。因此，我们建议在宿主-寄生虫相互作用过程中鉴定和表征组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶靶向的宿主分子(通路)。这项建议的具体目的是：1.研究杜氏乳杆菌组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶在转化生长因子和IL-10依赖途径中的协同作用。鉴定和鉴定杜氏乳杆菌组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶靶向的宿主分子。发现参与防御利什曼病的宿主分子(途径)可能会彻底改变治疗利什曼病和其他感染性病原体的药物和疫苗的开发方式。

Leishmania parasites are causative agents of leishmaniasis in humans. Leishmania donovani complex cause visceral leishmaniasis and account for over 500,000 new cases and 59,000 deaths every year. Although several potential vaccine candidates have been identified, there are no vaccines for leishmaniasis. In addition, emergence of drug resistance is another major problem in leishmaniasis control. Leishmania modulates immune response and the parasite factors involved and detailed mechanism of modulation of host immune system and signaling pathways are not fully understood. Cysteine proteases are potential drug and vaccine candidates implicated in modulation of host immune system and signaling pathways. Interleukin 10 (IL-10) and transforming growth factor beta (TGF-ß) are the major pro-inflammatory cytokines produced during Leishmania pathogenesis to escape microbicidal activities of the host. Although parasite cysteine proteases have been implicated in the process, the specific host molecules targeted and the detailed mechanisms are not yet determined. However, activation of TGF-ß1 due to cleavage of pre-TGF-ß1 in vitro by L. chagasi cathepsin B cysteine proteases has been reported from our lab although its significance in survival and pathogenesis is not yet determined. Thus, we propose to identify and characterize host molecules (pathways) targeted by L. donovani cathepsin B and cathepsin L cysteine proteases during host-parasite interaction. The specific aims of this proposal are to: 1.) Study the concerted role of L. donovani cathepsin B and cathepsin L cysteine proteases in TGF-ß and IL-10 dependant pathways and 2.) Identify and characterize host molecules targeted by L. donovani cathepsin B and cathepsin L cysteine proteases. Discovering host molecules (pathways) involved in defense against leishmaniasis could revolutionize the way drugs and vaccines are developed against leishmaniasis and other infectious agents.