PATHOGENESIS OF HUMAN GRANULOCYTIC EHRLICHIOSIS

描述(改编自申请人的摘要)：人粒细胞 埃立克体病(Hge)是一种急性发热性疾病，2年前在 明尼苏达州和威斯康星州，现在迅速出现在其出没的地区 很可能是媒介，硬壳类壁虱。HGE出现在血粒细胞中，导致 白细胞和血小板计数的抑制，可导致严重的 并发症。诊断一直很困难，血清学检测，使用 感染相关马埃立克体的马的白细胞，是 在表达上不够敏感。申请人最近分离出了病原学 通过在HL60细胞中培养来自患者的HGE试剂(Goodman等， 1996年)。此外，申请人还种植了E.equi(Munderloh等人， 1996)，现在在我的肩胛骨细胞系中，它发展成不同的 比在人类细胞中形成的更多。这些发现为研究提供了基础 旨在更好地了解该毒剂的生物学特性。在他的实验室里， HGE现在也已经在其推定的天然靶细胞--人骨中生长 同时感染粒细胞和单核细胞的骨髓祖细胞 以及前身。申请人的研究也有力地表明唾液酸 Lewis x(CD15s)是一种主要的细胞，它存在于两种细胞上 HGE的表面受体。该试剂表现出独特的铁/铁载体。 相互作用，并且似乎能够在内体内存活。我。 用培养的人疱疹病毒感染肩部，用于扁虱叮咬感染 仓鼠(导致血液发现与人类相似)。这个 然后从受感染的仓鼠身上重新分离出该病毒，完成其生命周期。 基于HGE的IFA和免疫印迹分析已经开发出来，开始定义 主要免疫原，它们在感染期间的时间演变，以及可能的 扁虱和人类细胞中抗原表达的差异。在一个 在疫区，申请者已经组成了一个多学科团队来建设 在这些进步的基础上迅速发展。古德曼博士的目标是：1)描述， 在分子水平上，HGE试剂与其人类 靶细胞和受体(S)，2)表征生物学关键 HGE与其TICK载体和体外培养的TICK细胞的相互作用及比较 这些与人类细胞中定义的基因的相互作用以及3)识别和 猪瘟病毒主要抗原蛋白的特性及其免疫应答 这些抗原。

DESCRIPTION (Adapted from the applicant's abstract): Human granulocytic ehrlichiosis (HGE) is an acute febrile illness described 2 years ago in Minnesota and Wisconsin and now rapidly emerging in areas infested by its likely vector, Ixodes ticks. HGE appears in blood granulocytes, causes depression of leukocyte and platelet counts, and can result in serious complications. Diagnosis has been difficult and serologic testing, using leukocytes from horses infected with the related Ehrlichia equi, is insensitive at presentation. The applicant recently isolated the etiologic agent of HGE from patients by cultivation in HL60 cells (Goodman, et al, 1996). In addition, the applicant has grown E. equi (Munderloh et al, 1996), and now HGE, in I. scapularis cell lines, where it develops different forms than in human cells. These findings provided the basis for studies aimed at better understanding the biology of the agent. In his laboratory, HGE has now also been grown in its presumed natural target cells, human bone marrow progenitors, with infection of both granulocytic and monocytic cells and precursors. The applicant's studies also strongly suggest that sialyl Lewis x (CD15s), which is present on both cell types, is a major cell surface receptor for HGE. The agent manifests unique iron/siderophore interactions and appears capable of survival within endosomes. I. scapularis was infected with cultured HGE and used to tick bite infect hamsters (resulting in blood findings similar to those in humans). The agent was then reisolated from infected hamsters, completing its life-cycle. HGE-based IFA and immunoblot assays have been developed to begin to define major immunogens, their temporal evolution during infection, and possible differences in antigenic expression in tick vs. human cells. Working in an endemic area, the applicant has formed a multidisciplinary team to build rapidly upon these advances. Dr. Goodman's aims are: 1) to characterize, at the molecular level, the interaction of the HGE agent with both its human target cells and receptor(s), 2) to characterize the biologically critical interaction of HGE with its tick vector and cultured tick cells and compare these interactions with those defined in human cells and 3) to identify and characterize the key antigenic proteins of HGE and the immune response to these antigens.