MONOCYTIC DIFFERENTIATION INHIBITS INFECTION AND GRANULOCYTIC DIFFERENTIATION POTENTIATES INFECTION BY THE AGENT OF HUMAN GRANULOCYTIC EHRLICHIOSIS

Human granulocytic ehrlichiosis (HGE) is an emerging tick-borne infect ion with a specific tropism for granulocytes. We previously isolated a nd cultivated the HGE agent in the promyelocytic leukemia cell line HL -60 and have also demonstrated the susceptibility of both granulocytic and monocytic human marrow progenitors. Circulating monocytes have no t been observed to be infected, suggesting that cell susceptibility ma y be differentiation specific, To evaluate this hypothesis, HL-60 cell s were differentiated towards granulocytes with dimethyl sulfoxide or all-trans retinoic acid) or toward monocytes-macrophages (with 12 0-te tradecanoylphorbol-13-acetate [TPA], gamma interferon, or 1,25-dihydro xyvitamin D-3) and then challenged with HGE. HGE binding, internalizat ion, and proliferation were compared in differentiated and untreated c ontrol HL-60 cells by immunofluorescence, electron microscopy, and Gie msa staining. Granulocytic differentiation resulted in a doubling of H GE binding and enhanced infection consistent with the agent's clinical tropism for neutrophils, Granulocytic cells were unable to kill inter nalized ehrlichiae even after activation induced by N-formyl-Met-Leu-P he alone or together with tumor necrosis factor alpha, In contrast, mo nocyte-macrophage differentiation with TPA resulted in complete resist ance to infection through at least two distinct mechanisms: (i) reduct ion in binding and uptake and (ii) killing of any internalized organis ms. Diminished binding in TPA-treated cells correlated with their redu ced expression of sialyl Lewis x (CD15s), a putative cellular receptor component for HGE, The degree of monocytic differentiation and activa tion induced (i.e., TPA > gamma interferon >vitamin D-3) correlated wi th resistance to HGE. Thus, HL-60 cells exhibit a striking differentia tion-specific susceptibility to HGE. Differentiation-induced changes i n bacterial adhesion and killing capacity underlie the tropism of HGE for granulocytic HL-60 cells and, conversely, the resistance of activa ted macrophages to infection.