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

点击翻译按钮获取中文摘要

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.