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Infection and Immunity, February 2002, p. 889-898, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.889-898.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rapid Activation of Protein Tyrosine Kinase and Phospholipase C-{gamma}2 and Increase in Cytosolic Free Calcium Are Required by Ehrlichia chaffeensis for Internalization and Growth in THP-1 Cells

Mingqun Lin,1 Michael X. Zhu,2 and Yasuko Rikihisa1*

Department of Veterinary Biosciences,1 Neurobiotechnology Center and Department of Neurosciences, The Ohio State University, Columbus, Ohio 432102

Received 2 July 2001/ Returned for modification 4 October 2001/ Accepted 24 October 2001

Ehrlichia chaffeensis, a bacterium that cannot survive outside the eukaryotic cell, proliferates exclusively in human monocytes and macrophages. In this study, signaling events required for ehrlichial infection of human monocytic cell line THP-1 were characterized. Entry and proliferation of E. chaffeensis in THP-1 cells were significantly blocked by various inhibitors that can regulate calcium signaling, including 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate and 2-aminoethoxydiphenyl borate (intracellular calcium mobilization inhibitors), verapamil and 1-{ß-[3-(4-methoxyphenyl)propyl]-4-methoxyphenethyl}-1H-imidazole (SKF-96365) (calcium channel inhibitors), neomycin and 1-(6-{[17ß-3-methoxyestra-1,3,5(10)-trien-17-yl]amino}hexyl)-1H-pyrrole-2,5-dione (U-73122) (phospholipase C [PLC] inhibitors), monodansylcadaverine (a transglutaminase [TGase] inhibitor), and genistein (a protein tyrosine kinase [PTK] inhibitor). Addition of E. chaffeensis resulted in rapid increases in the level of inositol 1,4,5-trisphosphate (IP3) and the level of cytosolic free calcium ([Ca2+]i) in THP-1 cells, which were prevented by pretreatment of THP-1 cells with inhibitors of TGase, PTK, and PLC. E. chaffeensis induced rapid tyrosine phosphorylation of PLC-{gamma}2, and the presence of a PLC-{gamma}2 antisense oligonucleotide in THP-1 cells significantly blocked ehrlichial infection. Furthermore, tyrosine-phosphorylated proteins and PLC-{gamma}2 were colocalized with ehrlichial inclusions, as determined by double-immunofluorescence labeling. The heat-sensitive component of viable E. chaffeensis cells was essential for these signaling events. E. chaffeensis, therefore, can recruit interacting signal-transducing molecules and induce the following signaling events required for the establishment of infection in host cells: protein cross-linking by TGase, tyrosine phosphorylation, PLC-{gamma}2 activation, IP3 production, and an increase in [Ca2+]i.

* Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210. Phone: (614) 292-9677. Fax: (614) 292-6473. E-mail: Rikihisa.1{at}osu.edu.

Editor: J. T. Barbieri

Infection and Immunity, February 2002, p. 889-898, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.889-898.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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