Abstract
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, gp91phox, and FACS analysis showed that plasma membrane-associated gp91phox protein was reduced on the infected cells. Infection with HGE organisms also decreased gp91phox 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 gp91phox, the first direct inhibition of NADPH oxidase by a pathogen.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Membrane / enzymology
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Down-Regulation / immunology
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Ehrlichia chaffeensis / immunology*
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Ehrlichiosis / immunology*
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Ehrlichiosis / metabolism*
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Ehrlichiosis / microbiology
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Gene Expression Regulation / immunology
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HL-60 Cells
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Humans
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Membrane Glycoproteins / antagonists & inhibitors*
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Mice
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Mice, Inbred C3H
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NADPH Oxidase 2
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NADPH Oxidases / biosynthesis
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NADPH Oxidases / genetics
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Neutrophils / enzymology
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Neutrophils / immunology*
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Neutrophils / metabolism
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Neutrophils / microbiology*
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Respiratory Burst / immunology*
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Superoxides / antagonists & inhibitors
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Superoxides / metabolism
Substances
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Membrane Glycoproteins
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RNA, Messenger
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Superoxides
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CYBB protein, human
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NADPH Oxidase 2
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NADPH Oxidases