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Infection and Immunity, March 2000, p. 1125-1133, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Intracellular Infection by the Human Granulocytic
Ehrlichiosis Agent Inhibits Human Neutrophil Apoptosis
Kiyotaka
Yoshiie,
Hyung-Yong
Kim,
Jason
Mott, and
Yasuko
Rikihisa*
Department of Veterinary Biosciences, The
Ohio State University, Columbus, Ohio 43210-1093
Received 13 August 1999/Returned for modification 7 October
1999/Accepted 23 November 1999
In patients with human granulocytic ehrlichiosis (HGE), the HGE
agent has been seen only in the peripheral blood granulocytes, which
have a life span too short for ehrlichial proliferation. To determine
if the HGE agent delays the apoptosis of human peripheral blood
neutrophils for its advantage, peripheral blood granulocytes consisting
mostly of neutrophils were incubated with freshly freed host cell-free
HGE agent in vitro. The HGE agent induced a significant delay in
morphological apoptosis and the cytoplasmic appearance of
histone-associated DNA fragments in the granulocytes. This antiapoptotic effect was dose dependent. Although much weaker than the
HGE agent freshly freed from the host cells, noninfectious purified HGE
agent stored frozen and thawed also had antiapoptotic effect, which was
lost with proteinase K treatment but not with periodate treatment.
Treatment of neutrophils with a transglutaminase inhibitor,
monodansylcadaverine, blocked the antiapoptotic effect of the HGE
agent. Addition of oxytetracycline, however, did not prevent or reverse
the antiapoptotic effect of the HGE agent. These results suggest that
binding of a protein component(s) of the HGE agent to neutrophils and
subsequent cross-linking and/or internalization of the receptor and
ehrlichiae are required for antiapoptotic signaling, but ehrlichial
protein synthesis and/or proliferation is not required. MG-132, a
proteasome inhibitor, and cycloheximide accelerated the apoptosis of
neutrophils and overrode the antiapoptotic effect of the HGE agent.
Studies with specific inhibitors suggest that protein kinase A,
NF-
B, and interleukin 1
are not involved in the antiapoptotic
mechanism of the HGE agent.
*
Corresponding author. Mailing address: Department of
Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd., Columbus, OH 43210-1093. Phone: (614) 292-5661. Fax: (614) 292-6473. E-mail: rikihisa.1{at}osu.edu.

Present address: Department of Bacteriology, Faculty of Medicine,
Kagoshima University, Kagoshima 890-8520,
Japan.
Infection and Immunity, March 2000, p. 1125-1133, Vol. 68, No. 3
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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