PATHOGENESIS OF HUMAN GRANULOCYTIC EHRLICHIOSIS

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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.