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引起内脏利什曼病，每年有超过500，000例新发病例和59，000例死亡。虽然已经确定了几种潜在的候选疫苗，但没有针对利什曼病的疫苗。此外，抗药性的出现是控制利什曼病的另一个主要问题。利什曼原虫调节免疫应答和参与的寄生虫因子，以及调节宿主免疫系统和信号通路的详细机制尚未完全了解。半胱氨酸蛋白酶是潜在的药物和疫苗候选物，涉及调节宿主免疫系统和信号传导途径。白细胞介素10（IL-10）和转化生长因子β（TGF-β）是利什曼原虫发病过程中产生的主要促炎细胞因子，以逃避宿主的杀微生物活性。虽然寄生虫半胱氨酸蛋白酶已牵连的过程中，具体的宿主分子的目标和详细的机制尚未确定。然而，由于前TGF-β 1在体外被L.查加斯组织蛋白酶B半胱氨酸蛋白酶已从我们的实验室报告，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宿主分子（途径）的目标L。donovani组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶。本提案的具体目标是：1）研究了L. donovani组织蛋白酶B和组织蛋白酶L半胱氨酸蛋白酶在TGF-β和IL-10依赖性途径中的作用，和2.）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。发现宿主分子（途径）参与防御利什曼病可能会彻底改变药物和疫苗的方式开发针对利什曼病和其他传染性病原体。

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.