Trichomonas pathogenesis: cell surface interactions

描述（由申请方提供）：阴道毛滴虫是全球最常见的非病毒性传播感染（STI）的病原体，也是美国人群中最常见的寄生虫。增加传播艾滋病毒的妇女慢性感染这种寄生虫和最近增加的耐药毛滴虫病的发病率，保证更好地了解这种未充分研究的病原体的生物学。7.在美国内城，迷走神经感染还与早产、低出生体重和婴儿死亡率增加有关。尽管其全球医学重要性，T。流浪汉实际上是未知的。我们已经证明了这种寄生虫表面的糖萼在宿主细胞粘附和细胞毒性中的作用，并确定了第一个假定的7迷走神经的宿主细胞受体。我们现在提出表征7表面上的分子。阴道上皮细胞和人阴道上皮细胞（VEC）可能是宿主-寄生虫相互作用的关键。为此，我们建议（1）阐明野生型和突变体7的结构。迷走神经表面糖缀合物和脂磷酸聚糖（LPG）作为鉴定参与其组装的新酶的步骤，（2）缺失丝氨酸棕榈酰转移酶2（SPT 2）基因以产生LPG无效突变体并确定对寄生虫粘附和细胞毒性的影响（3）验证单糖鼠李糖合成和组装所需的候选7种迷走神经基因，宿主细胞中不存在的一种不寻常的糖，以及（4）检查7种迷走神经LPG和宿主细胞半乳糖凝集素-1（gal-1）之间的相互作用，并研究这种相互作用是否在发病机制中起作用。除了提供关于这种流行性传播感染的宿主-病原体相互作用机制的关键数据外，拟议的研究还将产生可能有助于开发新型药物疗法和疫苗接种策略的信息。

DESCRIPTION (provided by applicant): Trichomonas vaginalis is the etiologic agent of the most common non-viral sexually transmitted infection (STI) worldwide and is the most prevalent parasite found in the US population. Increased transmission of HIV in women chronically infected with this parasite and a recent increase in the incidence of drug resistant Trichomoniasis warrant a better understanding of the biology of this understudied pathogen. 7. vaginalis infections are also associated with pre-term delivery, low birth weight and increased infant mortality in inner city America. Despite its global medical importance, the molecular mechanisms underlying the pathogenesis of T. vaginalis are virtually unknown. We have demonstrated a role for the glycocalyx that coats the surface of this parasite in host cell adherence and cytotoxicity and have identified the first putative host cell receptor for 7 vaginalis. We now propose to characterize molecules on the surface of 7. vaginalis and human vaginal epithelia cells (VECs) that may be critical for host-parasite interactions. To this end, we propose to (1) elucidate the structure of wild-type and mutant 7. vaginalis surface glycoconjugates and lipophosphoglycan (LPG) as a step towards identifying novel enzymes involved in its assembly, (2) delete the serine palmitoyl transferase 2 (SPT2) gene to create LPG null mutants and determine the effect on adherence and cytotoxicity of the parasite (3) validate candidate7 vaginalis genes required for the synthesis and assembly of the monosaccharide rhamnose, an unusual sugar that is absent in host cells and (4) examine the interaction between 7 vaginalis LPG and host cell galectin-1 (gal-1) and investigate whether this interaction plays a role in pathogenesis. In addition to providing critical data on the mechanisms underlying host-pathogen interaction of this prevalent STI, the proposed studies will yield information that may be useful for developing novel drug therapies and vaccination strategies.