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。多诺瓦利什曼原虫复合体引起内脏利什曼病，每年造成50多万新病例和5.9万例死亡。虽然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，耐药性的出现是控制利什曼病的另一个主要问题。利什曼原虫可调节机体免疫应答，所涉及的寄生因子、调节宿主免疫系统的具体机制和信号通路尚不完全清楚。半胱氨酸蛋白酶是潜在的药物和疫苗候选人涉及调节宿主免疫系统和信号通路。白细胞介素10 （IL-10）和转化生长因子β （TGF-ß）是利什曼原虫发病过程中为逃避宿主杀微生物活性而产生的主要促炎细胞因子。虽然寄生虫半胱氨酸蛋白酶参与了这一过程，但具体的宿主分子和详细的机制尚未确定。然而，我们实验室已经报道了L. chagasi组织蛋白酶B半胱氨酸蛋白酶在体外裂解前TGF-ß1而激活TGF-ß1，但其在生存和发病机制中的意义尚未确定。因此，我们建议鉴定和表征L. donovani组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶在宿主-寄生虫相互作用过程中靶向的宿主分子（途径）。本提案的具体目标是：1)研究L. donovani组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶在TGF-ß和IL-10依赖通路中的协同作用；鉴定和表征L. donovani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）可能会彻底改变针对利什曼病和其他传染性病原体开发药物和疫苗的方式。

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.