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Cutting Edge: Infection by the Agent of Human Granulocytic Ehrlichiosis Prevents the Respiratory Burst by Down-Regulating gp91^phox1

Rila Banerjee^*, Juan Anguita^*, Dirk Roos and Erol Fikrig^2,*

^* Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and Central Laboratory of the Netherlands Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

The agent of human granulocytic ehrlichiosis (HGE) is an emerging tick-borne pathogen that resides in neutrophils and can be cultured in a promyelocytic (HL-60) cell line. In response to microbes, polymorphonuclear leukocytes normally activate the NADPH oxidase enzyme complex and generate superoxide anion (O₂^-). However, HL-60 cells infected with HGE bacteria did not produce O₂^- upon activation with PMA. RT-PCR demonstrated that HGE organisms inhibited mRNA expression of a single component of NADPH oxidase, gp91^phox, and FACS analysis showed that plasma membrane-associated gp91^phox protein was reduced on the infected cells. Infection with HGE organisms also decreased gp91^phox mRNA levels in splenic neutrophils in a murine model of HGE, demonstrating this phenomenon in vivo. Therefore, HGE bacteria repress the respiratory burst by down-regulating gp91^phox, the first direct inhibition of NADPH oxidase by a pathogen.