S. MANSONI HOMOLOGUES OF EGF RECEPTOR AND P-GLYCOPROTEIN

血吸虫病是一种慢性、使人衰弱的寄生虫病，影响 全球数亿人。 寄生虫是一种细胞外寄生虫 血吸虫可以存活多年而不在其体内复制 人类宿主。 由于蠕虫必须与其宿主密切相互作用， 正常执行营养吸收和附着等功能 由完整的表面膜蛋白执行，寄生虫必须具有 开发了避免针对这些蛋白质的免疫攻击的机制。 我们的长期目标是识别这些机制并尝试颠覆 重组表面膜免疫的有效性 蛋白质表位。 作为第一步，我们最近克隆了全长 编码 EGF 受体 (SER) 血吸虫同源物的 cDNA 和部分 编码哺乳动物两种不同血吸虫同源物的 cDNA 克隆 多重耐药因子、P-糖蛋白(SMDR1)、SMDR2)。 同时 研究SER表达，我们还发现血吸虫使用交替 剪接途径产生编码羧基的变体SER转录本 SER 的末端截短形式应被分泌和 膜锚定。 这些变异形式可能会调节免疫反应 对抗 SER 或结合抗体，否则可能会发生这种情况，但不会产生任何后果 会损害 寄生虫。 该提案的具体目的是广泛描述正常情况 不同SER和SMDR蛋白的表达和免疫原性。 SER和SMDR的表达将从转录方面进行研究， 生命周期中的时间安排和转录本的本地化 蛋白质产品。 全长的本地产品将在 哺乳动物细胞和针对这些蛋白质的抗体反应的比较 与受感染小鼠体内的情况相同。 抗血清和重组抗体 这些蛋白质上的肽表位将被生成并测试其 识别天然膜蛋白上的细胞外表位的能力 并抑制这些蛋白质的功能。 如果结果是 有望对其疫苗潜力进行体内测试。 这些研究应该为血吸虫的生物学提供新的见解 以及两个重要膜蛋白家族的分子进化。 在 此外，它们应为有关以下方面的其他研究提供基础： 使用血清暴露的血吸虫表面膜蛋白的潜力 作为疫苗靶标。

Schistosomiasis is a chronic, debilitating parasitic disease affecting hundreds of millions of people worldwide. The parasite is an extracellular blood fluke that can survive for many years without replicating in its human host. Since the worms must interact closely with their host, performing functions such as nutrient uptake and attachment normally performed by integral surface membrane proteins, the parasites must have developed mechanisms for avoiding immune attack directed at these proteins. Our long-range goal is to identify these mechanisms and attempt to subvert their effectiveness by immunization with recombinant surface membrane protein epitopes. As a first step, we have recently cloned a full-length cDNA encoding the schistosome homologue of EGF receptor (SER) and partial cDNA clones encoding two distinct schistosome homologues of the mammalian multi-drug resistance factor, P-glycoprotein (SMDR1), SMDR2). While studying SER expression, we also found that schistosomes use alternate splicing pathways to generate variant SER transcripts encoding carboxy- terminally truncated forms of SER that should be both secreted and membrane-anchored. These variant forms may modulate the immune response against SER or bind, without consequence, antibodies that might otherwise be damaging to the parasite. The specific aim of this proposal is to characterize extensively the normal expression and immunogenicity of the different SER and SMDR proteins. Expression of SER and SMDR will be studied in terms of transcription, timing during the life cycle and localization of their transcripts and protein products. Full-length, native products will be expressed within mammalian cells and the antibody response against these proteins compared to that within infected mice. Anti-sera and recombinant antibodies against peptide epitopes on these proteins will be generated and tested for their ability to recognize extracellular epitopes on the native membrane proteins and to inhibit the function of these proteins. If the results are promising, in vivo testing of their vaccine potential will be carried out. These studies should provide new insight into the biology of schistosomes and the molecular evolution of two important membrane protein families. In addition, they should provide the basis for additional studies concerning the potential of using serum-exposed schistosome surface membrane proteins as vaccine targets.