Trichomonas pathogenesis: cell surface interactions

描述（由申请人提供）：阴道毛滴虫是世界上最常见的非病毒性性传播感染（STI）的病原体，也是美国人口中发现的最普遍的寄生虫。长期感染这种寄生虫的妇女中艾滋病毒传播的增加以及最近耐药滴虫病发病率的增加，使人们有理由更好地了解这种尚未得到充分研究的病原体的生物学特性。7. 在美国市中心，阴道感染也与早产、低出生体重和婴儿死亡率增加有关。尽管其在全球医学上具有重要意义，但其发病机制的分子机制实际上是未知的。我们已经证明了覆盖在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，并已经确定了7阴道虫的第一个假定的宿主细胞受体。我们现在提议表征7表面的分子。阴道上皮细胞和人阴道上皮细胞（VECs）可能是宿主-寄生虫相互作用的关键。为此，我们建议：(1)阐明野生型和突变型7的结构。(2)删除丝氨酸棕榈酰转移酶2 （SPT2）基因以创建LPG零突变体，并确定对寄生虫的粘附性和细胞毒性的影响(3)验证合成和组装单糖鼠李糖所需的7个阴道基因候选基因。(4)检测7阴道液化气与宿主细胞半凝集素-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的性传播感染的宿主-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对开发新的药物治疗和疫苗接种策略有用的信息。

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.